U.S. patent number 8,425,907 [Application Number 13/325,098] was granted by the patent office on 2013-04-23 for methods for treating pruritus by administering an antibody that specifically binds human par2.
This patent grant is currently assigned to Regeneron Pharmaceuticals, Inc.. The grantee listed for this patent is Michael L. LaCroix-Fralish, Lynn MacDonald, Marc R. Morra, Andrew J. Murphy, Nicholas J. Papadopoulos, Robert R. Salzler. Invention is credited to Michael L. LaCroix-Fralish, Lynn MacDonald, Marc R. Morra, Andrew J. Murphy, Nicholas J. Papadopoulos, Robert R. Salzler.
United States Patent |
8,425,907 |
MacDonald , et al. |
April 23, 2013 |
Methods for treating pruritus by administering an antibody that
specifically binds human PAR2
Abstract
The present invention provides methods for treating pruritus by
blocking human protease activated receptor-2 (PAR2) activity. The
methods of the invention can be used to treat pruritus associated
with atopic dermatitis, psoriasis, burn scarring, hypertrophic
scarring, keloids, renal failure or hepatic failure. The methods of
the invention include administering an antibody or antigen-binding
fragment thereof that specifically binds human PAR2.
Inventors: |
MacDonald; Lynn (White Plains,
NY), Murphy; Andrew J. (Croton-on-Hudson, NY),
Papadopoulos; Nicholas J. (LaGrangeville, NY), Morra; Marc
R. (Beacon Falls, CT), Salzler; Robert R. (Durham,
NC), LaCroix-Fralish; Michael L. (Sleepy Hollow, NY) |
Applicant: |
Name |
City |
State |
Country |
Type |
MacDonald; Lynn
Murphy; Andrew J.
Papadopoulos; Nicholas J.
Morra; Marc R.
Salzler; Robert R.
LaCroix-Fralish; Michael L. |
White Plains
Croton-on-Hudson
LaGrangeville
Beacon Falls
Durham
Sleepy Hollow |
NY
NY
NY
CT
NC
NY |
US
US
US
US
US
US |
|
|
Assignee: |
Regeneron Pharmaceuticals, Inc.
(Tarrytown, NY)
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Family
ID: |
43063654 |
Appl.
No.: |
13/325,098 |
Filed: |
December 14, 2011 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20120093824 A1 |
Apr 19, 2012 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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12877133 |
Sep 8, 2010 |
8101724 |
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61240783 |
Sep 9, 2009 |
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61242821 |
Sep 16, 2009 |
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61317839 |
Mar 26, 2010 |
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Current U.S.
Class: |
424/139.1;
424/152.1 |
Current CPC
Class: |
A61P
1/00 (20180101); A61P 25/04 (20180101); A61P
43/00 (20180101); A61P 29/00 (20180101); A61K
39/3955 (20130101); A61P 35/00 (20180101); A61P
37/08 (20180101); A61P 37/00 (20180101); A61P
11/00 (20180101); A61P 17/04 (20180101); A61P
19/02 (20180101); C07K 16/28 (20130101); A61P
1/18 (20180101); A61P 19/04 (20180101); A61P
1/04 (20180101); A61P 17/00 (20180101); A61P
11/06 (20180101); A61K 45/06 (20130101); C07K
2317/76 (20130101); C07K 2317/21 (20130101); C07K
2317/34 (20130101); A61K 2039/505 (20130101); C07K
2317/24 (20130101) |
Current International
Class: |
A61K
39/00 (20060101); A61K 39/395 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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2009005726 |
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Jan 2009 |
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WO |
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2009096695 |
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Jun 2009 |
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WO |
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2009117481 |
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Sep 2009 |
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WO |
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2010147440 |
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Dec 2010 |
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WO |
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2010147441 |
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Dec 2010 |
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WO |
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2011000930 |
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Jun 2011 |
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WO |
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Other References
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-independent pathways in mice," J. Pharmacol. Sci. 108(3): 385-388
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applicant.
|
Primary Examiner: Landsman; Robert
Attorney, Agent or Firm: Westberg; Christopher B.
Cottingham; Frank R.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a divisional of U.S. application Ser. No.
12/877,133, filed on Sep. 8, 2010, now issued as U.S. Pat. No.
8,101,724, which claims the benefit under 35 U.S.C. .sctn.119(e) of
U.S. provisional application No. 61/240,783, filed on Sep. 9, 2009,
61/242,821, filed on Sep. 16, 2009, and 61/317,839, filed on Mar.
26, 2010, the disclosures of which are herein incorporated by
reference in their entireties.
Claims
What is claimed is:
1. A method for treating pruritus, the method comprising
administering to a patient in need thereof an effective amount of
an antibody or antigen-binding fragment thereof that specifically
binds human protease-activated receptor 2 (PAR2) (SEQ ID NO:851),
wherein the antibody or antigen-binding fragment thereof: (a)
interacts with Ser-37, Leu-38, Ile-39, Gly-40, Val-42 and Asp-43 of
human PAR2; (b) does not interact with Lys-41 of human PAR2; (c)
blocks trypsin cleavage of human PAR2 at the activating cleavage
site located at the junction of residues Arg-36 and Ser-37 of human
PAR2; (d) does not block trypsin cleavage of human PAR2 at the
non-activating cleavage site located at the junction of residues
Arg-31 and Ser-32; and (e) competes for binding to human PAR2 with
a reference antibody comprising heavy chain CDRs
(HCDR1-HCDR2-HCDR3) having the amino acid sequences of SEQ ID
NOs:700-702-704; and the light chain CDRs (LCDR1-LCDR2-LCDR3)
having the amino acid sequences of SEQ ID NOs:708-710-712.
2. The method of claim 1, wherein the pruritus is associated with
atopic dermatitis, psoriasis, burn scarring, hypertrophic scarring,
keloids, renal failure or hepatic failure.
3. The method of claim 1, wherein the antibody or antigen-binding
fragment comprises a heavy chain variable region (HCVR) and a light
chain variable region (LCVR)--, wherein the HCVR comprises the
heavy chain CDRs (HCDR1-HCDR2-HCDR3) having the amino acid
sequences of SEQ ID NOs:700-702-704, and wherein the LCVR comprises
the light chain CDRs (LCDR1-LCDR2-LCDR3) having the amino acid
sequences of SEQ ID NOs:708-710-712.
4. The method of claim 1, wherein the antibody or antigen-binding
fragment comprises a HCVR having the amino acid sequence of SEQ ID
NO:714 and a LCVR having the amino acid sequence of SEQ ID
NO:692.
5. The method of claim 1, wherein the antibody or antigen-binding
fragment thereof causes a dose-dependent reduction in scratching
behaviors when administered at a dose of at least 25 mg/kg to a
hPAR2+/+ mouse protease-induced pruritus model.
6. The method of claim 1, further comprising administering to the
patient one or more additional therapeutic agent(s) selected from
the group consisting of an IL-1 inhibitor, an IL-18 inhibitor, an
IL-4 inhibitor, an IL-4 receptor inhibitor, an IL-6 inhibitor, an
IL-6 receptor inhibitor, a nerve growth factor (NGF) inhibitor, a
tumor necrosis factor (TNF) inhibitor, a TNF receptor inhibitor, a
uric acid synthesis inhibitor and a corticosteroid.
Description
FIELD OF THE INVENTION
The present invention relates to antibodies, and antigen-binding
fragments thereof, which are specific for protease-activated
receptor-2 (PAR-2).
BACKGROUND
Protease-activated receptors ("PARs") are a family of
seven-transmembrane G-protein-coupled receptors. Among
seven-transmembrane G-protein-coupled receptors PARs have a unique
mode of activation; that is, PARs are activated by proteolytic
cleavage at the amino terminus to generate a new N-terminal domain
which serves as a "tethered ligand." The tethered ligand interacts
with the extracellular loop-2 of the receptor thereby resulting in
receptor activation. Currently, there are four known members of the
PAR family, designated PAR-1, PAR-2, PAR-3 and PAR-4.
PAR-2 has also been referred to as "C140." (see U.S. Pat. No.
5,874,400). Both human and murine PAR-2 share the protease cleavage
domain SKGRSLIG (residues 6-13 of SEQ ID NO:852, and residues 8-15
of SEQ ID NO:856). This sequence is cleaved between the R and S
residues by a variety of proteases such as trypsin, as well as by
mast cell tryptase, tissue factor/factor VIIa complex and factor
Xa, neutrophil proteinase 3 (PR-3), human leukocyte elastase, and
proteases originating from pathogenic organisms.
PAR-2 activity has been implicated in or associated with several
diseases and conditions including inflammatory diseases, pain,
gastrointestinal conditions, neurological diseases, and
cardiovascular disorders (see, e.g., Linder et al., 2000, J.
Immunol. 165:6504-6510; Vergnolle et al., 2001, Nature Medicine
7:821-826; Cenac et al., 2007, J. Clin. Investigation 117:636-647;
Vergnolle, 2004, British J. Pharmacol. 141:1264-1274; Knight et
al., 2001, J. Allergy Clin. Immunol. 108:797-803; Schmidlin et al.,
2002, J. Immunol. 169:5315-5321). Antibodies that bind to PAR-2
have the potential to antagonize the activity of PAR-2 in vivo.
Anti-PAR-2 antibodies are therefore potentially useful for treating
and/or ameliorating a variety of disease conditions.
Antibodies that bind to PAR-2, and certain therapeutic uses
thereof, are mentioned in U.S. Pat. No. 5,874,400, US 2007/0237759,
WO 2009/005726, and US 2010/0119506. Nonetheless, there remains a
need in the art for novel PAR-2 modulating agents, including
anti-PAR-2 antibodies, that can be used to treat PAR-2-mediated
diseases and conditions.
BRIEF SUMMARY OF THE INVENTION
The present invention provides human antibodies that bind to human
PAR-2. The antibodies of the invention are useful, inter alia, for
inhibiting PAR-2-mediated signaling and for treating diseases and
disorders caused by or related to PAR-2 activation.
The present invention includes antibodies which interact with the
N-terminal region of PAR-2 and block proteolytic cleavage at the
activating PAR-2 protease cleavage site (as defined herein) but do
not block proteolytic cleavage at one or more non-activating
protease cleavage sites. According to certain embodiments,
anti-PAR-2 antibodies which exhibit such proteolytic cleavage
blocking properties interact with specific amino acids in the
vicinity of the activating PAR-2 protease cleavage site. For
example, the present invention provides anti-PAR-2 antibodies with
protease cleavage blocking activity and which interact with Val-42
and Asp-43 of human PAR-2 (SEQ ID NO:851), and may further interact
with one or more human PAR-2 residues selected from the group
consisting of Ser-37, Leu-38, Ile-39, Gly-40, and Gly-44.
According to other embodiments, the anti-PAR-2 antibodies of the
present invention specifically bind to human PAR-2 and monkey PAR-2
but do not bind to at least one member selected from the group
consisting of mouse, rat, rabbit, dog and pig PAR-2. The present
invention also includes antibodies that are capable of inhibiting
or attenuating proteolytic activation of PAR-2 but do not block
proteolytic cleavage of PAR-2. Exemplary methods for
measuring/assessing an antibody's ability to block PAR-2 cleavage
or proteolytic activation are described herein.
The antibodies of the invention can be full-length (for example, an
IgG1 or IgG4 antibody) or may comprise only an antigen-binding
portion (for example, a Fab, F(ab').sub.2 or scFv fragment), and
may be modified to affect functionality, e.g., to eliminate
residual effector functions (Reddy et al., 2000, J. Immunol.
164:1925-1933).
The present invention provides an antibody or antigen-binding
fragment of an antibody comprising a heavy chain variable region
(HCVR) having an amino acid sequence selected from the group
consisting of SEQ ID NO: 2, 18, 22, 26, 42, 46, 50, 66, 70, 74, 90,
94, 98, 114, 118, 122, 138, 142, 146, 162, 166, 170, 186, 190, 194,
210, 214, 218, 234, 238, 242, 258, 262, 266, 282, 286, 290, 306,
310, 314, 330, 334, 338, 354, 358, 362, 378, 382, 386, 402, 406,
410, 426, 430, 434, 450, 454, 458, 474, 478, 482, 498, 502, 506,
522, 526, 530, 546, 550, 554, 570, 574, 578, 594, 598, 602, 618,
622, 626, 642, 646, 650, 666, 670, 674, 690, 694, 698, 714, 718,
722, 738, 742, 746, 762, 766, 770, 786, 790, 794, 810, 814, 818,
834, and 838, or a substantially similar sequence thereof having at
least 90%, at least 95%, at least 98% or at least 99% sequence
identity. According to certain embodiments, the antibody or
antigen-binding portion of an antibody comprises a HCVR having an
amino acid sequence selected from the group consisting of SEQ ID
NO: 98, 146, 338, and 714.
The present invention also provides an antibody or antigen-binding
fragment of an antibody comprising a light chain variable region
(LCVR) having an amino acid sequence selected from the group
consisting of SEQ ID NO: 10, 20, 24, 34, 44, 48, 58, 68, 72, 82,
92, 96, 106, 116, 120, 130, 140, 144, 154, 164, 168, 178, 188, 192,
202, 212, 216, 226, 236, 240, 250, 260, 264, 274, 284, 288, 298,
308, 312, 322, 332, 336, 346, 356, 360, 370, 380, 384, 394, 404,
408, 418, 428, 432, 442, 452, 456, 466, 476, 480, 490, 500, 504,
514, 524, 528, 538, 548, 552, 562, 572, 576, 586, 596, 600, 610,
620, 624, 634, 644, 648, 658, 668, 672, 682, 692, 696, 706, 716,
720, 730, 740, 744, 754, 764, 768, 778, 788, 792, 802, 812, 816,
826, 836, and 840, or a substantially similar sequence thereof
having at least 90%, at least 95%, at least 98% or at least 99%
sequence identity. According to certain embodiments, the antibody
or antigen-binding portion of an antibody comprises a LCVR having
an amino acid sequence selected from the group consisting of SEQ ID
NO: 106, 154, 346, and 692.
The present invention also provides an antibody or antigen-binding
fragment thereof comprising a HCVR and LCVR (HCVR/LCVR) sequence
pair selected from the group consisting of SEQ ID NO: 2/10, 18/20,
22/24, 26/34, 42/44, 46/48, 50/58, 66/68, 70/72, 74/82, 90/92,
94/96, 98/106, 114/116, 118/120, 122/130, 138/140, 142/144,
146/154, 162/164, 166/168, 170/178, 186/188, 190/192, 194/202,
210/212, 214/216, 218/226, 234/236, 238/240, 242/250, 258/260,
262/264, 266/274, 282/284, 286/288, 290/298, 306/308, 310/312,
314/322, 330/332, 334/336, 338/346, 354/356, 358/360, 362/370,
378/380, 382/384, 386/394, 402/404, 406/408, 410/418, 426/428,
430/432, 434/442, 450/452, 454/456, 458/466, 474/476, 478/480,
482/490, 498/500, 502/504, 506/514, 522/524, 526/528, 530/538,
546/548, 550/552, 554/562, 570/572, 574/576, 578/586, 594/596,
598/600, 602/610, 618/620, 622/624, 626/634, 642/644, 646/648,
650/658, 666/668, 670/672, 674/682, 690/692, 694/696, 698/706,
714/716, 714/692, 718/720, 722/730, 738/740, 742/744, 746/754,
762/764, 766/768, 770/778, 786/788, 790/792, 794/802, 810/812,
814/816, 818/826, 834/836, and 838/840. According to certain
embodiments, the antibody or fragment thereof comprises a HCVR and
LCVR selected from the amino acid sequence pairs of SEQ ID NO:
98/106, 146/154, 338/346, and 714/692.
The present invention also provides an antibody or antigen-binding
fragment of an antibody comprising a heavy chain CDR3 (HCDR3)
domain having an amino acid sequence selected from the group
consisting of SEQ ID NO: 8, 32, 56, 80, 104, 128, 152, 176, 200,
224, 248, 272, 296, 320, 344, 368, 392, 416, 440, 464, 488, 512,
536, 560, 584, 608, 632, 656, 680, 704, 728, 752, 776, 800, and
824, or a substantially similar sequence thereof having at least
90%, at least 95%, at least 98% or at least 99% sequence identity;
and a light chain CDR3 (LCDR3) domain having an amino acid sequence
selected from the group consisting of SEQ ID NO: 16, 40, 64, 88,
112, 136, 160, 184, 208, 232, 256, 280, 304, 328, 352, 376, 400,
424, 448, 472, 496, 520, 544, 568, 592, 616, 640, 664, 688, 712,
736, 760, 784, 808, and 832, or a substantially similar sequence
thereof having at least 90%, at least 95%, at least 98% or at least
99% sequence identity.
In certain embodiments, the antibody or antigen-binding portion of
an antibody comprises a HCDR3/LCDR3 amino acid sequence pair
selected from the group consisting of SEQ ID NO: 8/16, 32/40,
56/64, 80/88, 104/112, 128/136, 152/160, 176/184, 200/208, 224/232,
248/256, 272/280, 296/304, 320/328, 344/352, 368/376, 392/400,
416/424, 440/448, 464/472, 488/496, 512/520, 536/544, 560/568,
584/592, 608/616, 632/640, 656/664, 680/688, 704/712, 728/736,
752/760, 776/784, 800/808, and 824/832. According to certain
embodiments, the antibody or antigen-binding portion of an antibody
comprises a HCDR3/LCDR3 amino acid sequence pair selected from the
group consisting of SEQ ID NO: 104/112, 152/160, 344/352 and
704/712. Non-limiting examples of anti-PAR-2 antibodies having
these HCDR3/LCDR3 pairs are the antibodies designated H4H588N,
H4H591N, H4H618N, and H4H581P, respectively.
The present invention also provides an antibody or fragment thereof
further comprising a heavy chain CDR1 (HCDR1) domain having an
amino acid sequence selected from the group consisting of SEQ ID
NO: 4, 28, 52, 76, 100, 124, 148, 172, 196, 220, 244, 268, 292,
316, 340, 364, 388, 412, 436, 460, 484, 508, 532, 556, 580, 604,
628, 652, 676, 700, 724, 748, 772, 796, and 820, or a substantially
similar sequence thereof having at least 90%, at least 95%, at
least 98% or at least 99% sequence identity; a heavy chain CDR2
(HCDR2) domain having an amino acid sequence selected from the
group consisting of SEQ ID NO: 6, 30, 54, 78, 102, 126, 150, 174,
198, 222, 246, 270, 294, 318, 342, 366, 390, 414, 438, 462, 486,
510, 534, 558, 582, 606, 630, 654, 678, 702, 726, 750, 774, 798,
and 822, or a substantially similar sequence thereof having at
least 90%, at least 95%, at least 98% or at least 99% sequence
identity; a light chain CDR1 (LCDR1) domain having an amino acid
sequence selected from the group consisting of SEQ ID NO: 12, 36,
60, 84, 108, 132, 156, 180, 204, 228, 252, 276, 300, 324, 348, 372,
396, 420, 444, 468, 492, 516, 540, 564, 588, 612, 636, 660, 684,
708, 732, 756, 780, 804, and 828, or a substantially similar
sequence thereof having at least 90%, at least 95%, at least 98% or
at least 99% sequence identity; and a light chain CDR2 (LCDR2)
domain having an amino acid sequence selected from the group
consisting of SEQ ID NO: 14, 38, 62, 86, 110, 134, 158, 182, 206,
230, 254, 278, 302, 326, 350, 374, 398, 422, 446, 470, 494, 518,
542, 566, 590, 614, 638, 662, 686, 710, 734, 758, 782, 806, and
830, or a substantially similar sequence thereof having at least
90%, at least 95%, at least 98% or at least 99% sequence
identity.
Certain non-limiting, exemplary antibodies and antigen-binding
fragments of the invention comprise HCDR1, HCDR2, HCDR3, LCDR1,
LCDR2 and LCDR3 domains, respectively, selected from the group
consisting of: (i) SEQ ID NO: 100, 102, 104, 108, 110 and 112
(e.g., H4H588N); (ii) SEQ ID NO: 148, 150, 152, 156, 158 and 160
(e.g., H4H591N); (iii) SEQ ID NO: 340, 342, 344, 348, 350 and 352
(e.g., H4H618N); and (iv) SEQ ID NO: 700, 702, 704, 708, 710 and
712 (e.g., H4H581P). The amino acid sequences of these exemplary
CDRs are depicted in FIGS. 2 and 3.
In a related embodiment, the invention comprises an antibody or
antigen-binding fragment of an antibody which specifically binds
PAR-2, wherein the antibody or fragment comprises the heavy and
light chain CDR domains contained within heavy and light chain
sequences selected from the group consisting of SEQ ID NO: 2/10,
18/20, 22/24, 26/34, 42/44, 46/48, 50/58, 66/68, 70/72, 74/82,
90/92, 94/96, 98/106, 114/116, 118/120, 122/130, 138/140, 142/144,
146/154, 162/164, 166/168, 170/178, 186/188, 190/192, 194/202,
210/212, 214/216, 218/226, 234/236, 238/240, 242/250, 258/260,
262/264, 266/274, 282/284, 286/288, 290/298, 306/308, 310/312,
314/322, 330/332, 334/336, 338/346, 354/356, 358/360, 362/370,
378/380, 382/384, 386/394, 402/404, 406/408, 410/418, 426/428,
430/432, 434/442, 450/452, 454/456, 458/466, 474/476, 478/480,
482/490, 498/500, 502/504, 506/514, 522/524, 526/528, 530/538,
546/548, 550/552, 554/562, 570/572, 574/576, 578/586, 594/596,
598/600, 602/610, 618/620, 622/624, 626/634, 642/644, 646/648,
650/658, 666/668, 670/672, 674/682, 690/692, 694/696, 698/706,
714/716, 714/692, 718/720, 722/730, 738/740, 742/744, 746/754,
762/764, 766/768, 770/778, 786/788, 790/792, 794/802, 810/812,
814/816, 818/826, 834/836, and 838/840. According to certain
embodiments, the antibody or fragment thereof comprises the CDR
sequences contained within HCVRs and LCVRs selected from the amino
acid sequence pairs of SEQ ID NO: 98/106, 146/154, 338/346, and
714/692. Methods and techniques for identifying CDRs within HCVR
and LCVR amino acid sequences are well known in the art and can be
used to identify CDRs within the specified HCVR and/or LCVR amino
acid sequences disclosed herein. Exemplary conventions that can be
used to identify the boundaries of CDRs include, e.g., the Kabat
definition, the Chothia definition, and the AbM definition. In
general terms, the Kabat definition is based on sequence
variability, the Chothia definition is based on the location of the
structural loop regions, and the AbM definition is a compromise
between the Kabat and Chothia approaches. See, e.g., Kabat,
"Sequences of Proteins of Immunological Interest," National
Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J.
Mol. Biol. 273:927-948 (1997); and Martin et al., Proc. Natl. Acad.
Sci. USA 86:9268-9272 (1989). Public databases are also available
for identifying CDR sequences within an antibody.
In another aspect, the invention provides nucleic acid molecules
encoding anti-PAR-2 antibodies or fragments thereof. Recombinant
expression vectors carrying the nucleic acids of the invention, and
host cells into which such vectors have been introduced, are also
encompassed by the invention, as are methods of producing the
antibodies by culturing the host cells under conditions permitting
production of the antibodies, and recovering the antibodies
produced.
In one embodiment, the invention provides an antibody or fragment
thereof comprising a HCVR encoded by a nucleic acid sequence
selected from the group consisting of SEQ ID NO: 1, 17, 21, 25, 41,
45, 49, 65, 69, 73, 89, 93, 97, 113, 117, 121, 137, 141, 145, 161,
165, 169, 185, 189, 193, 209, 213, 217, 233, 237, 241, 257, 261,
265, 281, 285, 289, 305, 309, 313, 329, 333, 337, 353, 357, 361,
377, 381, 385, 401, 405, 409, 425, 429, 433, 449, 453, 457, 473,
477, 481, 497, 501, 505, 521, 525, 529, 545, 549, 553, 569, 573,
577, 593, 597, 601, 617, 621, 625, 641, 645, 649, 665, 669, 673,
689, 693, 697, 713, 717, 721, 737, 741, 745, 761, 765, 769, 785,
789, 793, 809, 813, 817, 833, and 837, or a substantially identical
sequence having at least 90%, at least 95%, at least 98%, or at
least 99% homology thereof. According to certain embodiments, the
antibody or fragment thereof comprises a HCVR encoded by a nucleic
acid sequence selected from the group consisting of SEQ ID NO: 97,
145, 337, and 713.
The present invention also provides an antibody or fragment thereof
comprising a LCVR encoded by a nucleic acid sequence selected from
the group consisting of SEQ ID NO: 9, 19, 23, 33, 43, 47, 57, 67,
71, 81, 91, 95, 105, 115, 119, 129, 139, 143, 153, 163, 167, 177,
187, 191, 201, 211, 215, 225, 235, 239, 249, 259, 263, 273, 283,
287, 297, 307, 311, 321, 331, 335, 345, 355, 359, 369, 379, 383,
393, 403, 407, 417, 427, 431, 441, 451, 455, 465, 475, 479, 489,
499, 503, 513, 523, 527, 537, 547, 551, 561, 571, 575, 585, 595,
599, 609, 619, 623, 633, 643, 647, 657, 667, 671, 681, 691, 695,
705, 715, 719, 729, 739, 743, 753, 763, 767, 777, 787, 791, 801,
811, 815, 825, 835, and 839, or a substantially identical sequence
having at least 90%, at least 95%, at least 98%, or at least 99%
homology thereof. According to certain embodiments, the antibody or
fragment thereof comprises a LCVR encoded by a nucleic acid
sequence selected from the group consisting of SEQ ID NO: 105, 153,
345, and 715.
The present invention also provides an antibody or antigen-binding
fragment of an antibody comprising a HCDR3 domain encoded by a
nucleotide sequence selected from the group consisting of SEQ ID
NO: 7, 31, 55, 79, 103, 127, 151, 175, 199, 223, 247, 271, 295,
319, 343, 367, 391, 415, 439, 463, 487, 511, 535, 559, 583, 607,
631, 655, 679, 703, 727, 751, 775, 799, and 823, or a substantially
identical sequence having at least 90%, at least 95%, at least 98%,
or at least 99% homology thereof; and a LCDR3 domain encoded by a
nucleotide sequence selected from the group consisting of SEQ ID
NO: 15, 39, 63, 87, 111, 135, 159, 183, 207, 231, 255, 279, 303,
327, 351, 375, 399, 423, 447, 471, 495, 519, 543, 567, 591, 615,
639, 663, 687, 711, 735, 759, 783, 807, and 831, or a substantially
identical sequence having at least 90%, at least 95%, at least 98%,
or at least 99% homology thereof. According to certain embodiments,
the antibody or fragment thereof comprises HCDR3 and LCDR3
sequences encoded by the nucleic acid sequence pairs selected from
the group consisting of SEQ ID NO: 103/111, 151/159, 343/351, and
703/711.
The present invention also provides an antibody or fragment thereof
which further comprises a HCDR1 domain encoded by a nucleotide
sequence selected from the group consisting of SEQ ID NO: 3, 27,
51, 75, 99, 123, 147, 171, 195, 219, 243, 267, 291, 315, 339, 363,
387, 411, 435, 459, 483, 507, 531, 555, 579, 603, 627, 651, 675,
699, 723, 747, 771, 795, and 819, or a substantially identical
sequence having at least 90%, at least 95%, at least 98%, or at
least 99% homology thereof; a HCDR2 domain encoded by a nucleotide
sequence selected from the group consisting of SEQ ID NO: 5, 29,
53, 77, 101, 125, 149, 173, 197, 221, 245, 269, 293, 317, 341, 365,
389, 413, 437, 461, 485, 509, 533, 557, 581, 605, 629, 653, 677,
701, 725, 749, 773, 797, and 821, or a substantially identical
sequence having at least 90%, at least 95%, at least 98%, or at
least 99% homology thereof; a LCDR1 domain encoded by a nucleotide
sequence selected from the group consisting of SEQ ID NO: 11, 35,
59, 83, 107, 131, 155, 179, 203, 227, 251, 275, 299, 323, 347, 371,
395, 419, 443, 467, 491, 515, 539, 563, 587, 611, 635, 659, 683,
707, 731, 755, 779, 803, and 827, or a substantially identical
sequence having at least 90%, at least 95%, at least 98%, or at
least 99% homology thereof; and a LCDR2 domain encoded by a
nucleotide sequence selected from the group consisting of SEQ ID
NO: 13, 37, 61, 85, 109, 133, 157, 181, 205, 229, 253, 277, 301,
325, 349, 373, 397, 421, 445, 469, 493, 517, 541, 565, 589, 613,
637, 661, 685, 709, 733, 757, 781, 805, 829, or a substantially
identical sequence having at least 90%, at least 95%, at least 98%,
or at least 99% homology thereof.
According to certain embodiments, the antibody or fragment thereof
comprises the heavy and light chain CDR sequences encoded by the
nucleic acid sequences of SEQ ID NO: 97 and 105; SEQ ID NO: 145 and
153; SEQ ID NO: 337 and 345; or SEQ ID NO: 713 and 715.
The present invention also provides an isolated antibody or
antigen-binding fragment of an antibody that specifically binds
PAR-2, comprising a HCDR3 and a LCDR3, wherein the HCDR3 comprises
an amino acid sequence of the formula
X.sup.1-X.sup.2-X.sup.3-X.sup.4-X.sup.5-X.sup.6-X.sup.7-X.sup.8-X.sup.9-X-
.sup.10- X.sup.11-X.sup.12 (SEQ ID NO:843) wherein X.sup.1 is Ala
or Val, X.sup.2 is Lys, X.sup.3 is Gly or Glu, X.sup.4 is Asp or
Gly, X.sup.5 is Phe or Asp, X.sup.6 is Trp or Ser, X.sup.7 is Ser
or Gly, X.sup.8 is Gly or Tyr, X.sup.9 is Tyr or Asp, X.sup.10 is
Phe or Leu, X.sup.11 is Asp or Ala, and X.sup.12 is Tyr; and the
LCDR3 comprises an amino acid sequence of the formula
X.sup.1-X.sup.2-X.sup.3-X.sup.4-X.sup.5-X.sup.6-X.sup.7-X.sup.8-X.sup.9
(SEQ ID NO:846) wherein X.sup.1 is Met or Gln, X.sup.2 is Gln,
X.sup.3 is Ala or Tyr, X.sup.4 is Thr or Lys, X.sup.5 is Gln, Ser
or Ile, X.sup.6 is Phe or Ser, X.sup.7 is Pro, X.sup.8 is Thr or
Leu, and X.sup.9 is Thr or absent.
In a more specific embodiment, the invention features an isolated
antibody or fragment thereof that specifically binds PAR-2,
comprising a HCDR1 sequence of the formula
X.sup.1-X.sup.2-X.sup.3-X.sup.4-X.sup.5-X.sup.6-X.sup.7-X.sup.8
(SEQ ID NO:841), wherein X.sup.1 is Gly, X.sup.2 is Phe, X.sup.3 is
Thr, X.sup.4 is Phe, X.sup.5 is Ser or Arg, X.sup.6 is Ser or Arg,
X.sup.7 is Tyr, and X.sup.8 is Gly, Ala or Thr; a HCDR2 sequence of
the formula
X.sup.1-X.sup.2-X.sup.3-X.sup.4-X.sup.5-X.sup.6-X.sup.7-X.sup.8
(SEQ ID NO:842), wherein X.sup.1 is Ile, X.sup.2 is Ser, Gly or
Thr, X.sup.3 is Tyr, Gly or Asp, X.sup.4 is Asp, Gly or Ser,
X.sup.5 is Gly or Arg, X.sup.6 is Ile, Gly or Ala, X.sup.7 is Asn,
Ser, Arg or Gly, and X.sup.8 is Lys, Ala or Thr; a HCDR3 sequence
of the formula
X.sup.1-X.sup.2-X.sup.3-X.sup.4-X.sup.5-X.sup.6-X.sup.7-X.sup.8-X.sup.9-X-
.sup.10-X.sup.11-X.sup.12 (SEQ ID NO:843) wherein X.sup.1 is Ala or
Val, X.sup.2 is Lys, X.sup.3 is Gly or Glu, X.sup.4 is Asp or Gly,
X.sup.5 is Phe or Asp, X.sup.6 is Trp or Ser, X.sup.7 is Ser or
Gly, X.sup.8 is Gly or Tyr, X.sup.9 is Tyr or Asp, X.sup.10 is Phe
or Leu, X.sup.11 is Asp or Ala, and X.sup.12 is Tyr; a LCDR1
sequence of the formula
X.sup.1-X.sup.2-X.sup.3-X.sup.4-X.sup.5-X.sup.6-X.sup.7-X.sup.8-X.sup.9-X-
.sup.10-X.sup.11 (SEQ ID NO:844) wherein X.sup.1 is Gln, X.sup.2 is
Ser or Gly, X.sup.3 is Leu or Ile, X.sup.4 is Val or Ser, X.sup.5
is His, Asn or Thr, X.sup.6 is Ser, Asn or Tyr, X.sup.7 is Asp or
absent; X.sup.8 is Gly or absent, X.sup.9 is Asn or absent,
X.sup.10 is Thr or absent, and X.sup.11 is Tyr or absent; a LCDR2
sequence of the formula X.sup.1-X.sup.2-X.sup.3 (SEQ ID NO:845)
wherein X.sup.1 is Lys or Ala, X.sup.2 is Ile, Ala or Thr, and
X.sup.3 is Ser; and a LCDR3 comprises an amino acid sequence of the
formula
X.sup.1-X.sup.2-X.sup.3-X.sup.4-X.sup.5-X.sup.6-X.sup.7-X.sup.8-X.sup.9
(SEQ ID NO:846) wherein X.sup.1 is Met or Gln, X.sup.2 is Gln,
X.sup.3 is Ala or Tyr, X.sup.4 is Thr or Lys, X.sup.5 is Gln, Ser
or Ile, X.sup.6 is Phe or Ser, X.sup.7 is Pro, X.sup.8 is Thr or
Leu, and X.sup.9 is Thr or absent.
The invention encompasses anti-PAR-2 antibodies having a modified
glycosylation pattern. In some applications, modification to remove
undesirable glycosylation sites may be useful, or an antibody
lacking a fucose moiety present on the oligosaccharide chain, for
example, to increase antibody dependent cellular cytotoxicity
(ADCC) function (see Shield et al. (2002) JBC 277:26733). In other
applications, modification of galactosylation can be made in order
to modify complement dependent cytotoxicity (CDC).
In another aspect, the invention provides a pharmaceutical
composition comprising a recombinant human antibody or fragment
thereof which specifically binds PAR-2 and a pharmaceutically
acceptable carrier. In a related aspect, the invention features a
composition which is a combination of a PAR-2 inhibitor and a
second therapeutic agent. In one embodiment, the PAR-2 inhibitor is
an antibody or fragment thereof. In one embodiment, the second
therapeutic agent is any agent that is advantageously combined with
a PAR-2 inhibitor. Exemplary agents that may be advantageously
combined with a PAR-2 inhibitor include, without limitation, other
agents that inhibit PAR-2 activity (including other antibodies or
antigen-binding fragments thereof, peptide inhibitors, small
molecule antagonists, etc) and/or agents which interfere with PAR-2
upstream or downstream signaling.
In yet another aspect, the invention provides methods for
inhibiting PAR-2 activity using the anti-PAR-2 antibody or
antigen-binding portion of an antibody of the invention, wherein
the therapeutic methods comprise administering a therapeutically
effective amount of a pharmaceutical composition comprising an
antibody or antigen-binding fragment of an antibody of the
invention. The disorder treated is any disease or condition which
is improved, ameliorated, inhibited or prevented by removal,
inhibition or reduction of PAR-2 activity. The anti-PAR-2 antibody
or antibody fragment of the invention may function to block the
interaction between PAR-2 and a protease (e.g., trypsin or
trypsin-like serine proteases) or otherwise inhibit
protease-mediated activation of PAR-2. Alternatively, or
additionally, the anti-PAR-2 antibodies of the invention may
interfere with the interaction between the PAR-2 tethered ligand
and one or more of the PAR-2 extracellular loops (see, e.g.,
MacFarlane et al., 2001, Pharmacological Reviews 53:245-282 for a
general discussion of PAR-2 proteolytic cleavage and activation).
The antibody or antibody fragment may be used alone or in
combination with one or more additional therapeutic agents.
The present invention also includes the use of an anti-PAR-2
antibody or antigen binding portion of an antibody of the invention
in the manufacture of a medicament for the treatment of a disease
or disorder related to or caused by PAR-2 activity in a
patient.
Other embodiments will become apparent from a review of the ensuing
detailed description.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1. Sequence comparison table of heavy chain variable regions
and CDRs of antibodies H1H581P, H2M588N, H2M591N and H2M618N.
FIG. 2. Sequence comparison table of light chain variable regions
and CDRs of antibodies H1H581P, H2M588N, H2M591N and H2M618N.
FIGS. 3A and B. The top panel (A) shows C- and N-terminal biotin
labeled peptides corresponding to the sequence surrounding the
activating PAR-2 protease cleavage site (GTNRSSKGRSLIGKVDGT; SEQ ID
NO:852). The protease cleavage sites are designated by number 1 (an
upstream, non-activating protease cleavage site) and number 2 (the
activating PAR-2 protease cleavage site). The expected sizes of the
uncleaved and cleaved fragments are indicated in the top table. The
bottom panel (B) shows the fragment sizes that were observed
following 0, 5, and 15 minutes of trypsin treatment in the presence
of anti-PAR-2 antibodies or negative control.
FIGS. 4A and B. The top panel (A) shows the mouse, rat and human
peptides corresponding to the sequence surrounding the activating
PAR-2 protease cleavage sites (SEQ ID NOs:883, 858 and 852,
respectively). The protease cleavage sites are designated by
numbers 1 and 2 (upstream, non-activating protease cleavage sites)
and number 3 (the activating PAR-2 protease cleavage site). The
expected sizes of the uncleaved and cleaved fragments are indicated
in the top table. The bottom panel (B) shows the fragment sizes
that were observed following 0 and 5 minutes of trypsin treatment
in the presence of anti-PAR-2 antibodies or negative control.
FIG. 5. Depiction of alanine scanning epitope mapping results for
antibody binding to the sequence surrounding the PAR-2 activating
protease cleavage site (SEQ ID NO:852). Open triangles represent
protease cleavage sites located upstream from the activating PAR-2
protease cleavage site. The activating PAR-2 protease cleavage site
is designated by a closed triangle. The numbers in parentheses
indicate the amino acid numbering in the full-length human PAR-2
sequence (SEQ ID NO:851). Numbers in circles under the amino acid
residues indicate the percent of T1/2 of antibody binding to
alanine-scan mutant peptide relative to the T1/2 of antibody
binding to wild-type peptide, as shown in Tables 24-26 and 28. If
duplicate experiments were conducted, the average T1/2 percentage
is shown in the circle. Black circles with white numbers indicate
amino acids that, when changed to alanine, reduce the T1/2 of
antibody binding to 30% or less of the T1/2 of antibody binding to
wild-type peptide. Such amino acids are defined herein as residues
with which the antibody interacts.
DETAILED DESCRIPTION
Before the present invention is described, it is to be understood
that this invention is not limited to particular methods and
experimental conditions described, as such methods and conditions
may vary. It is also to be understood that the terminology used
herein is for the purpose of describing particular embodiments
only, and is not intended to be limiting, since the scope of the
present invention will be limited only by the appended claims.
Unless defined otherwise, all technical and scientific terms used
herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. As used
herein, the term "about," when used in reference to a particular
recited numerical value, means that the value may vary from the
recited value by no more than 1%. For example, as used herein, the
expression "about 100" includes 99 and 101 and all values in
between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
Although any methods and materials similar or equivalent to those
described herein can be used in the practice or testing of the
present invention, the preferred methods and materials are now
described. All patents, applications and non-patent publications
mentioned in this specification are incorporated herein by
reference in their entireties.
Definitions
As used herein, the terms "proteinase-activated receptor-2,"
"protease-activated receptor-2," and "PAR-2", refer to full-length
PAR-2 protein. Human PAR-2 is encoded by the nucleic acid sequence
shown in SEQ ID NO:850 and has the amino acid sequence of SEQ ID
NO:851. Amino acid sequences of PAR-2 molecules from non-human
species (e.g., mouse, monkey, rabbit, dog, pig, etc.) are available
from public sources.
The term "PAR-2 fragment," as used herein, means a peptide or
polypeptide comprising 4, 5, 6, 7, 8, 9, 10 or more contiguous
amino acids located upstream from (i.e., N-terminal to) the
activating PAR-2 protease cleavage site (as defined herein below)
and/or 4, 5, 6, 7, 8, 9, 10 or more contiguous amino acids located
downstream from (i.e., C-terminal to) the activating PAR-2 protease
cleavage site. Exemplary PAR-2 fragments are illustrated in Example
2, Table 2 (designated Peptides "A" through "J"; i.e., SEQ ID
NOs:852 through 861, respectively).
The expressions "PAR-2" and "PAR-2 fragment," as used herein refer
to the human PAR-2 protein or fragment unless specified as being
from a non-human species (e.g., "mouse PAR-2," mouse PAR-2
fragment," "monkey PAR-2," "monkey PAR-2 fragment," etc.).
As used in the context of the present disclosure, the expression
"activating PAR-2 protease cleavage site" means the junction of
residues Arg-36 and Ser-37 of human PAR-2 (SEQ ID NO:851). The
activating PAR-2 protease cleavage site is the site which, when
cleaved, results in the formation of the PAR-2 tethered ligand in
the naturally occurring protein.
The term "PAR-2 protease," as used herein, means an enzyme which is
capable of cleaving a PAR-2 or PAR-2 fragment at the activating
PAR-2 protease cleavage site. Exemplary PAR-2 proteases include
trypsin, cathepsin G, acrosin, tissue factor VIIa, tissue factor
Xa, human airway trypsin-like protease, tryptase, membrane-type
serine protease-1 (MT-SP1), TMPRSS2, protease-3, elastase,
kallikrein-5, kallikrein-6, kallikrein-14, activated protein C,
duodenase, gingipains-R, Der p1, Der p3, Der p9, thermolysin,
serralysin, and T. denticla protease.
The term "antibody", as used herein, is intended to refer to
immunoglobulin molecules comprising four polypeptide chains, two
heavy (H) chains and two light (L) chains inter-connected by
disulfide bonds, as well as multimers thereof (e.g., IgM). Each
heavy chain comprises a heavy chain variable region (abbreviated
herein as HCVR or V.sub.H) and a heavy chain constant region. The
heavy chain constant region comprises three domains, C.sub.H1,
C.sub.H2 and C.sub.H3. Each light chain comprises a light chain
variable region (abbreviated herein as LCVR or V.sub.L) and a light
chain constant region. The light chain constant region comprises
one domain (C.sub.L1). The V.sub.H and V.sub.L regions can be
further subdivided into regions of hypervariability, termed
complementarity determining regions (CDRs), interspersed with
regions that are more conserved, termed framework regions (FR).
Each V.sub.H and V.sub.L is composed of three CDRs and four FRs,
arranged from amino-terminus to carboxy-terminus in the following
order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different
embodiments of the invention, the FRs of the anti-Ang-2 antibody
(or antigen-binding portion thereof) may be identical to the human
germline sequences, or may be naturally or artificially modified.
An amino acid consensus sequence may be defined based on a
side-by-side analysis of two or more CDRs.
The term "antibody," as used herein, also includes antigen-binding
fragments of full antibody molecules. The terms "antigen-binding
portion" of an antibody, "antigen-binding fragment" of an antibody,
and the like, as used herein, include any naturally occurring,
enzymatically obtainable, synthetic, or genetically engineered
polypeptide or glycoprotein that specifically binds an antigen to
form a complex. Antigen-binding fragments of an antibody may be
derived, e.g., from full antibody molecules using any suitable
standard techniques such as proteolytic digestion or recombinant
genetic engineering techniques involving the manipulation and
expression of DNA encoding antibody variable and optionally
constant domains. Such DNA is known and/or is readily available
from, e.g., commercial sources, DNA libraries (including, e.g.,
phage-antibody libraries), or can be synthesized. The DNA may be
sequenced and manipulated chemically or by using molecular biology
techniques, for example, to arrange one or more variable and/or
constant domains into a suitable configuration, or to introduce
codons, create cysteine residues, modify, add or delete amino
acids, etc.
Non-limiting examples of antigen-binding fragments include: (i) Fab
fragments; (ii) F(ab').sub.2 fragments; (iii) Fd fragments; (iv) Fv
fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb
fragments; and (vii) minimal recognition units consisting of the
amino acid residues that mimic the hypervariable region of an
antibody (e.g., an isolated complementarity determining region
(CDR)). Other engineered molecules, such as diabodies, triabodies,
tetrabodies and minibodies, are also encompassed within the
expression "antigen-binding fragment," as used herein.
An antigen-binding fragment of an antibody will typically comprise
at least one variable domain. The variable domain may be of any
size or amino acid composition and will generally comprise at least
one CDR which is adjacent to or in frame with one or more framework
sequences. In antigen-binding fragments having a V.sub.H domain
associated with a V.sub.L domain, the V.sub.H and V.sub.L domains
may be situated relative to one another in any suitable
arrangement. For example, the variable region may be dimeric and
contain V.sub.H-V.sub.H, V.sub.H-V.sub.L or V.sub.L-V.sub.L dimers.
Alternatively, the antigen-binding fragment of an antibody may
contain a monomeric V.sub.H or V.sub.L domain.
In certain embodiments, an antigen-binding fragment of an antibody
may contain at least one variable domain covalently linked to at
least one constant domain. Non-limiting, exemplary configurations
of variable and constant domains that may be found within an
antigen-binding fragment of an antibody of the present invention
include: (i) V.sub.H-C.sub.H1; (ii) V.sub.H-C.sub.H2; (iii)
V.sub.H-C.sub.H3; (iv) V.sub.H-C.sub.H1-C.sub.H2; (v)
V.sub.H-C.sub.H1-C.sub.H2-C.sub.H3; (vi) V.sub.H-C.sub.H2-C.sub.H3;
(vii) V.sub.H-C.sub.L; (viii) V.sub.L-C.sub.H1; (ix)
V.sub.L-C.sub.H2; (x) V.sub.L-C.sub.H3; (xi)
V.sub.L-C.sub.H1-C.sub.H2; (xii)
V.sub.L-C.sub.H1-C.sub.H2-C.sub.H3; (Xiii)
V.sub.L-C.sub.H2-C.sub.H3; and (xiv) V.sub.L-C.sub.L. In any
configuration of variable and constant domains, including any of
the exemplary configurations listed above, the variable and
constant domains may be either directly linked to one another or
may be linked by a full or partial hinge or linker region. A hinge
region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or
more) amino acids which result in a flexible or semi-flexible
linkage between adjacent variable and/or constant domains in a
single polypeptide molecule. Moreover, an antigen-binding fragment
of an antibody of the present invention may comprise a homo-dimer
or hetero-dimer (or other multimer) of any of the variable and
constant domain configurations listed above in non-covalent
association with one another and/or with one or more monomeric
V.sub.H or V.sub.L domain (e.g., by disulfide bond(s)).
As with full antibody molecules, antigen-binding fragments may be
monospecific or multispecific (e.g., bispecific). A multispecific
antigen-binding fragment of an antibody will typically comprise at
least two different variable domains, wherein each variable domain
is capable of specifically binding to a separate antigen or to a
different epitope on the same antigen. Any multispecific antibody
format, including the exemplary bispecific antibody formats
disclosed herein, may be adapted for use in the context of an
antigen-binding fragment of an antibody of the present invention
using routine techniques available in the art.
The constant region of an antibody is important in the ability of
an antibody to fix complement and mediate cell-dependent
cytotoxicity. Thus, the isotype of an antibody may be selected on
the basis of whether it is desirable for the antibody to mediate
cytotoxicity.
The term "human antibody", as used herein, is intended to include
antibodies having variable and constant regions derived from human
germline immunoglobulin sequences. The human antibodies of the
invention may include amino acid residues not encoded by human
germline immunoglobulin sequences (e.g., mutations introduced by
random or site-specific mutagenesis in vitro or by somatic mutation
in vivo), for example in the CDRs and in particular CDR3. However,
the term "human antibody", as used herein, is not intended to
include antibodies in which CDR sequences derived from the germline
of another mammalian species, such as a mouse, have been grafted
onto human framework sequences.
The term "recombinant human antibody", as used herein, is intended
to include all human antibodies that are prepared, expressed,
created or isolated by recombinant means, such as antibodies
expressed using a recombinant expression vector transfected into a
host cell (described further below), antibodies isolated from a
recombinant, combinatorial human antibody library (described
further below), antibodies isolated from an animal (e.g., a mouse)
that is transgenic for human immunoglobulin genes (see e.g., Taylor
et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies
prepared, expressed, created or isolated by any other means that
involves splicing of human immunoglobulin gene sequences to other
DNA sequences. Such recombinant human antibodies have variable and
constant regions derived from human germline immunoglobulin
sequences. In certain embodiments, however, such recombinant human
antibodies are subjected to in vitro mutagenesis (or, when an
animal transgenic for human Ig sequences is used, in vivo somatic
mutagenesis) and thus the amino acid sequences of the VH and VL
regions of the recombinant antibodies are sequences that, while
derived from and related to human germline VH and VL sequences, may
not naturally exist within the human antibody germline repertoire
in vivo.
Human antibodies can exist in two forms that are associated with
hinge heterogeneity. In one form, an immunoglobulin molecule
comprises a stable four chain construct of approximately 150-160
kDa in which the dimers are held together by an interchain heavy
chain disulfide bond. In a second form, the dimers are not linked
via inter-chain disulfide bonds and a molecule of about 75-80 kDa
is formed composed of a covalently coupled light and heavy chain
(half-antibody). These forms have been extremely difficult to
separate, even after affinity purification.
The frequency of appearance of the second form in various intact
IgG isotypes is due to, but not limited to, structural differences
associated with the hinge region isotype of the antibody. A single
amino acid substitution in the hinge region of the human IgG4 hinge
can significantly reduce the appearance of the second form (Angal
et al. (1993) Molecular Immunology 30:105) to levels typically
observed using a human IgG1 hinge. The instant invention
encompasses antibodies having one or more mutations in the hinge,
C.sub.H2 or C.sub.H3 region which may be desirable, for example, in
production, to improve the yield of the desired antibody form.
An "isolated antibody," as used herein, means an antibody that has
been identified and separated and/or recovered from at least one
component of its natural environment. For example, an antibody that
has been separated or removed from at least one component of an
organism, tissue or cell in which the antibody naturally exists or
is naturally produced is an "isolated antibody" for purposes of the
present invention. An isolated antibody also includes an antibody
in situ within a recombinant cell, as well as an antibody that has
been subjected to at least one purification or isolation step.
According to certain embodiments, an isolated antibody may be
substantially free of other cellular material and/or chemicals.
The term "specifically binds," or the like, means that an antibody
or antigen-binding fragment thereof forms a complex with an antigen
that is relatively stable under physiologic conditions. Specific
binding can be characterized by a dissociation constant of
1.times.10.sup.-6 M or less. Methods for determining whether two
molecules specifically bind are well known in the art and include,
for example, equilibrium dialysis, surface plasmon resonance, and
the like. For example, an antibody that "specifically binds" human
PAR-2, as used in the context of the present invention, includes
antibodies that bind human PAR-2 or portion thereof (e.g., a PAR-2
fragment comprising the activating protease cleavage site) with a
K.sub.D of less than about 1000 nM, less than about 500 nM, less
than about 300 nM, less than about 200 nM, less than about 100 nM,
less than about 90 nM, less than about 80 nM, less than about 70
nM, less than about 60 nM, less than about 50 nM, less than about
40 nM, less than about 30 nM, less than about 20 nM, less than
about 10 nM, less than about 5 nM, less than about 4 nM, less than
about 3 nM, less than about 2 nM, less than about 1 nM or less than
about 0.5 nM, as measured in a surface plasmon resonance assay.
(See, e.g., Example 4, herein). An isolated antibody that
specifically binds human PAR-2 may, however, have cross-reactivity
to other antigens, such as PAR-2 molecules from other species.
A "neutralizing" or "blocking" antibody, as used herein, is
intended to refer to an antibody whose binding to PAR-2: (i)
interferes with the interaction between PAR-2 or a PAR-2 fragment
and one or more proteases, (ii) prevents cleavage of PAR-2 or a
PAR-2 fragment by a PAR-2 protease, (iii) inhibits the interaction
between the PAR-2 tethered ligand and a PAR-2 extracellular loop,
and/or (iv) results in inhibition of at least one biological
function of PAR-2. The inhibition caused by a PAR-2 neutralizing or
blocking antibody need not be complete so long as it is detectable
using an appropriate assay. Exemplary assays for detecting PAR-2
inhibition are described herein.
The fully-human anti-PAR-2 antibodies disclosed herein may comprise
one or more amino acid substitutions, insertions and/or deletions
in the framework and/or CDR regions of the heavy and light chain
variable domains as compared to the corresponding germline
sequences. Such mutations can be readily ascertained by comparing
the amino acid sequences disclosed herein to germline sequences
available from, for example, public antibody sequence databases.
The present invention includes antibodies, and antigen-binding
fragments thereof, which are derived from any of the amino acid
sequences disclosed herein, wherein one or more amino acids within
one or more framework and/or CDR regions are back-mutated to the
corresponding germline residue(s) or to a conservative amino acid
substitution (natural or non-natural) of the corresponding germline
residue(s) (such sequence changes are referred to herein as
"germline back-mutations"). A person of ordinary skill in the art,
starting with the heavy and light chain variable region sequences
disclosed herein, can easily produce numerous antibodies and
antigen-binding fragments which comprise one or more individual
germline back-mutations or combinations thereof. In certain
embodiments, all of the framework and/or CDR residues within the
V.sub.H and/or V.sub.L domains are mutated back to the germline
sequence. In other embodiments, only certain residues are mutated
back to the germline sequence, e.g., only the mutated residues
found within the first 8 amino acids of FR1 or within the last 8
amino acids of FR4, or only the mutated residues found within CDR1,
CDR2 or CDR3. Furthermore, the antibodies of the present invention
may contain any combination of two or more germline back-mutations
within the framework and/or CDR regions, i.e., wherein certain
individual residues are mutated back to the germline sequence while
certain other residues that differ from the germline sequence are
maintained. Once obtained, antibodies and antigen-binding fragments
that contain one or more germline back-mutations can be easily
tested for one or more desired property such as, improved binding
specificity, increased binding affinity, improved or enhanced
antagonistic or agonistic biological properties (as the case may
be), reduced immunogenicity, etc. Antibodies and antigen-binding
fragments obtained in this general manner are encompassed within
the present invention.
The present invention also includes anti-PAR-2 antibodies
comprising variants of any of the HCVR, LCVR, and/or CDR amino acid
sequences disclosed herein having one or more conservative
substitutions. For example, the present invention includes
anti-PAR-2 antibodies having HCVR, LCVR, and/or CDR amino acid
sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or
fewer, etc. conservative amino acid substitutions relative to any
of the HCVR, LCVR, and/or CDR amino acid sequences disclosed
herein. In one embodiment, the antibody comprises an HCVR having
the amino acid sequence of SEQ ID NO:698 with 8 or fewer
conservative amino acid substitutions. In another embodiment, the
antibody comprises an HCVR having the amino acid sequence of SEQ ID
NO:698 with 6 or fewer conservative amino acid substitutions. In
another embodiment, the antibody comprises an HCVR having the amino
acid sequence of SEQ ID NO:698 with 4 or fewer conservative amino
acid substitutions. In another embodiment, the antibody comprises
an HCVR having the amino acid sequence of SEQ ID NO:698 with 2 or
fewer conservative amino acid substitutions. In one embodiment, the
antibody comprises an LCVR having the amino acid sequence of SEQ ID
NO:706 with 8 or fewer conservative amino acid substitutions. In
another embodiment, the antibody comprises an LCVR having the amino
acid sequence of SEQ ID NO:706 with 6 or fewer conservative amino
acid substitutions. In another embodiment, the antibody comprises
an LCVR having the amino acid sequence of SEQ ID NO:706 with 4 or
fewer conservative amino acid substitutions. In another embodiment,
the antibody comprises an LCVR having the amino acid sequence of
SEQ ID NO:706 with 2 or fewer conservative amino acid
substitutions.
The term "surface plasmon resonance", as used herein, refers to an
optical phenomenon that allows for the analysis of real-time
interactions by detection of alterations in protein concentrations
within a biosensor matrix, for example using the BIAcore.TM. system
(Biacore Life Sciences division of GE Healthcare, Piscataway,
N.J.).
The term "K.sub.D", as used herein, is intended to refer to the
equilibrium dissociation constant of a particular antibody-antigen
interaction.
The term "epitope" refers to an antigenic determinant that
interacts with a specific antigen binding site in the variable
region of an antibody molecule known as a paratope. A single
antigen may have more than one epitope. Thus, different antibodies
may bind to different areas on an antigen and may have different
biological effects. Epitopes may be either conformational or
linear. A conformational epitope is produced by spatially
juxtaposed amino acids from different segments of the linear
polypeptide chain. A linear epitope is one produced by adjacent
amino acid residues in a polypeptide chain. In certain
circumstance, an epitope may include moieties of saccharides,
phosphoryl groups, or sulfonyl groups on the antigen.
The term "substantial identity" or "substantially identical," when
referring to a nucleic acid or fragment thereof, indicates that,
when optimally aligned with appropriate nucleotide insertions or
deletions with another nucleic acid (or its complementary strand),
there is nucleotide sequence identity in at least about 95%, and
more preferably at least about 96%, 97%, 98% or 99% of the
nucleotide bases, as measured by any well-known algorithm of
sequence identity, such as FASTA, BLAST or Gap, as discussed below.
A nucleic acid molecule having substantial identity to a reference
nucleic acid molecule may, in certain instances, encode a
polypeptide having the same or substantially similar amino acid
sequence as the polypeptide encoded by the reference nucleic acid
molecule.
As applied to polypeptides, the term "substantial similarity" or
"substantially similar" means that two peptide sequences, when
optimally aligned, such as by the programs GAP or BESTFIT using
default gap weights, share at least 95% sequence identity, even
more preferably at least 98% or 99% sequence identity. Preferably,
residue positions which are not identical differ by conservative
amino acid substitutions. A "conservative amino acid substitution"
is one in which an amino acid residue is substituted by another
amino acid residue having a side chain (R group) with similar
chemical properties (e.g., charge or hydrophobicity). In general, a
conservative amino acid substitution will not substantially change
the functional properties of a protein. In cases where two or more
amino acid sequences differ from each other by conservative
substitutions, the percent sequence identity or degree of
similarity may be adjusted upwards to correct for the conservative
nature of the substitution. Means for making this adjustment are
well-known to those of skill in the art. See, e.g., Pearson (1994)
Methods Mol. Biol. 24: 307-331, herein incorporated by reference.
Examples of groups of amino acids that have side chains with
similar chemical properties include (1) aliphatic side chains:
glycine, alanine, valine, leucine and isoleucine; (2)
aliphatic-hydroxyl side chains: serine and threonine; (3)
amide-containing side chains: asparagine and glutamine; (4)
aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5)
basic side chains: lysine, arginine, and histidine; (6) acidic side
chains: aspartate and glutamate, and (7) sulfur-containing side
chains are cysteine and methionine. Preferred conservative amino
acids substitution groups are: valine-leucine-isoleucine,
phenylalanine-tyrosine, lysine-arginine, alanine-valine,
glutamate-aspartate, and asparagine-glutamine. Alternatively, a
conservative replacement is any change having a positive value in
the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992)
Science 256: 1443-1445, herein incorporated by reference. A
"moderately conservative" replacement is any change having a
nonnegative value in the PAM250 log-likelihood matrix.
Sequence similarity for polypeptides, which is also referred to as
sequence identity, is typically measured using sequence analysis
software. Protein analysis software matches similar sequences using
measures of similarity assigned to various substitutions, deletions
and other modifications, including conservative amino acid
substitutions. For instance, GCG software contains programs such as
Gap and Bestfit which can be used with default parameters to
determine sequence homology or sequence identity between closely
related polypeptides, such as homologous polypeptides from
different species of organisms or between a wild type protein and a
mutein thereof. See, e.g., GCG Version 6.1. Polypeptide sequences
also can be compared using FASTA using default or recommended
parameters, a program in GCG Version 6.1. FASTA (e.g., FASTA2 and
FASTA3) provides alignments and percent sequence identity of the
regions of the best overlap between the query and search sequences
(Pearson (2000) supra). Another preferred algorithm when comparing
a sequence of the invention to a database containing a large number
of sequences from different organisms is the computer program
BLAST, especially BLASTP or TBLASTN, using default parameters. See,
e.g., Altschul et al. (1990) J. Mol. Biol. 215:403-410 and Altschul
et al. (1997) Nucleic Acids Res. 25:3389-402, each herein
incorporated by reference.
Preparation of Human Antibodies
Methods for generating monoclonal antibodies, including fully human
monoclonal antibodies are known in the art. Any such known methods
can be used in the context of the present invention to make human
antibodies that specifically bind to human PAR-2.
Using VELOCIMMUNE.TM. technology or any other known method for
generating monoclonal antibodies, high affinity chimeric antibodies
to PAR-2 are initially isolated having a human variable region and
a mouse constant region. As in the experimental section below, the
antibodies are characterized and selected for desirable
characteristics, including affinity, selectivity, epitope, etc. The
mouse constant regions are replaced with a desired human constant
region to generate the fully human antibody of the invention, for
example wild-type or modified IgG1 or IgG4. While the constant
region selected may vary according to specific use, high affinity
antigen-binding and target specificity characteristics reside in
the variable region.
Bioequivalents
The anti-PAR-2 antibodies and antibody fragments of the present
invention encompass proteins having amino acid sequences that vary
from those of the described antibodies, but that retain the ability
to bind human PAR-2. Such variant antibodies and antibody fragments
comprise one or more additions, deletions, or substitutions of
amino acids when compared to parent sequence, but exhibit
biological activity that is essentially equivalent to that of the
described antibodies. Likewise, the anti-PAR-2 antibody-encoding
DNA sequences of the present invention encompass sequences that
comprise one or more additions, deletions, or substitutions of
nucleotides when compared to the disclosed sequence, but that
encode an anti-PAR-2 antibody or antibody fragment that is
essentially bioequivalent to an anti-PAR-2 antibody or antibody
fragment of the invention. Examples of such variant amino acid and
DNA sequences are discussed above.
Two antigen-binding proteins, or antibodies, are considered
bioequivalent if, for example, they are pharmaceutical equivalents
or pharmaceutical alternatives whose rate and extent of absorption
do not show a significant difference when administered at the same
molar dose under similar experimental conditions, either single
does or multiple dose. Some antibodies will be considered
equivalents or pharmaceutical alternatives if they are equivalent
in the extent of their absorption but not in their rate of
absorption and yet may be considered bioequivalent because such
differences in the rate of absorption are intentional and are
reflected in the labeling, are not essential to the attainment of
effective body drug concentrations on, e.g., chronic use, and are
considered medically insignificant for the particular drug product
studied.
In one embodiment, two antigen-binding proteins are bioequivalent
if there are no clinically meaningful differences in their safety,
purity, and potency.
In one embodiment, two antigen-binding proteins are bioequivalent
if a patient can be switched one or more times between the
reference product and the biological product without an expected
increase in the risk of adverse effects, including a clinically
significant change in immunogenicity, or diminished effectiveness,
as compared to continued therapy without such switching.
In one embodiment, two antigen-binding proteins are bioequivalent
if they both act by a common mechanism or mechanisms of action for
the condition or conditions of use, to the extent that such
mechanisms are known.
Bioequivalence may be demonstrated by in vivo and in vitro methods.
Bioequivalence measures include, e.g., (a) an in vivo test in
humans or other mammals, in which the concentration of the antibody
or its metabolites is measured in blood, plasma, serum, or other
biological fluid as a function of time; (b) an in vitro test that
has been correlated with and is reasonably predictive of human in
vivo bioavailability data; (c) an in vivo test in humans or other
mammals in which the appropriate acute pharmacological effect of
the antibody (or its target) is measured as a function of time; and
(d) in a well-controlled clinical trial that establishes safety,
efficacy, or bioavailability or bioequivalence of an antibody.
Bioequivalent variants of anti-PAR-2 antibodies of the invention
may be constructed by, for example, making various substitutions of
residues or sequences or deleting terminal or internal residues or
sequences not needed for biological activity. For example, cysteine
residues not essential for biological activity can be deleted or
replaced with other amino acids to prevent formation of unnecessary
or incorrect intramolecular disulfide bridges upon renaturation. In
other contexts, bioequivalent antibodies may include anti-PAR-2
antibody variants comprising amino acid changes which modify the
glycosylation characteristics of the antibodies, e.g., mutations
which eliminate or remove glycosylation.
Biological Characteristics of the Antibodies
The antibodies of the present invention may function through
complement-dependent cytotoxicity (CDC) or antibody-dependent
cell-mediated cytotoxicity (ADCC). "Complement-dependent
cytotoxicity" (CDC) refers to lysis of antigen-expressing cells by
an antibody of the invention in the presence of complement.
"Antibody-dependent cell-mediated cytotoxicity" (ADCC) refers to a
cell-mediated reaction in which nonspecific cytotoxic cells that
express Fc receptors (FcRs) (e.g., Natural Killer (NK) cells,
neutrophils, and macrophages) recognize bound antibody on a target
cell and thereby lead to lysis of the target cell. CDC and ADCC can
be measured using assays that are well known and available in the
art. (See, e.g., U.S. Pat. Nos. 5,500,362 and 5,821,337, and Clynes
et al. (1998) Proc. Natl. Acad. Sci. (USA) 95:652-656).
Alternatively, or additionally, the antibodies of the invention may
be therapeutically useful in blocking a PAR-2 interaction or
inhibiting receptor component interaction. In the case of the PAR-2
antibodies of the present invention, the antibodies may function
by, inter alia, blocking or obscuring the activating PAR-2 protease
cleavage site. Alternatively, the antibodies of the invention may
function by interfering with the interaction between the tethered
ligand and one or more extracellular loops (e.g., loop-1, loop-2
and/or loop-3).
More specifically, the anti-PAR-2 antibodies of the invention may
exhibit one or more of the following characteristics: (1) ability
to bind to a human PAR-2 or human PAR-2 fragment and to a non-human
(e.g., mouse, monkey, rat, rabbit, dog, pig, etc.) PAR-2 or PAR-2
fragment; (2) ability to bind to a human PAR-2 or human PAR-2
fragment but not to a non-human (e.g., mouse, monkey, rat, rabbit,
dog, pig, etc.) PAR-2 or PAR-2 fragment; (3) ability to bind to a
human PAR-2 or human PAR-2 fragment and to a monkey PAR-2 or monkey
PAR-2 fragment, but not to a mouse, rat, rabbit, dog or pig PAR-2
or PAR-2 fragment; (4) ability to bind to a human PAR-2 or human
PAR-2 fragment and to a human PAR-1, PAR-3 or PAR-4 or fragment
thereof; (5) ability to bind to a human PAR-2 or human PAR-2
fragment but not to a human PAR-1, PAR-3, or PAR-4 or fragment
thereof; (6) ability to bind to a human PAR-2 or human PAR-2
fragment and to a non-human (e.g., mouse, monkey, rat, rabbit, dog,
pig, etc.) PAR-1, PAR-3 or PAR-4 or fragment thereof; (7) ability
to bind to a human PAR-2 or human PAR-2 fragment but not to a
non-human (e.g., mouse, monkey, rat, rabbit, dog, pig, etc.) PAR-1,
PAR-3 or PAR-4 or fragment thereof; (8) ability to block
proteolytic cleavage of a PAR-2 or a PAR-2 fragment; (9) ability to
block proteolytic cleavage of a human PAR-2 or human PAR-2 fragment
and a non-human (e.g., mouse, monkey, rat, rabbit, dog, pig, etc.)
PAR-2 or PAR-2 fragment; (10) ability to block proteolytic cleavage
of a human PAR-2 or human PAR-2 fragment but not a non-human (e.g.,
mouse, monkey, rat, rabbit, dog, pig, etc.) PAR-2 or PAR-2
fragment; (11) ability to block proteolytic cleavage of a human
PAR-2 or human PAR-2 fragment and a human PAR-1, PAR-3 or PAR-4 or
fragment thereof; (12) ability to block proteolytic cleavage of a
human PAR-2 or human PAR-2 fragment but not a human PAR-1, PAR-3 or
PAR-4 or fragment thereof; (13) ability to block proteolytic
cleavage of a human PAR-2 or human PAR-2 fragment and a non-human
(e.g., mouse, monkey, rat, rabbit, dog, pig, etc.) PAR-1, PAR-3 or
PAR-4 or fragment thereof; and/or (14) ability to block proteolytic
cleavage of a human PAR-2 or human PAR-2 fragment but not a
non-human (e.g., mouse, monkey, rat, rabbit, dog, pig, etc.) PAR-1,
PAR-3 or PAR-4 or fragment thereof.
As used in items (8)-(14) above, the term "proteolytic cleavage"
means cleavage of a PAR molecule (PAR-1, PAR-2, PAR-3 or PAR-4) or
fragment thereof by a PAR-2 protease or other enzyme that is
capable of cleaving PAR-2 at the activating PAR-2 protease cleavage
site.
The N-terminal region of human PAR-2 has at least two
"non-activating" protease cleavage sites, i.e., sites that are
capable of being cleaved by trypsin but do not result in activation
of the receptor. The N-terminal non-activating protease cleavage
sites are located: (a) at the junction of residues Arg-31 and
Ser-32 of human PAR-2 (SEQ ID NO:851); and (b) at the junction of
residues Lys-34 and Gly-35 of human PAR-2 (SEQ ID NO:851). The
activating and non-activating cleavage sites at the N-terminus of
PAR-2 are illustrated in FIG. 5 (white triangles indicate the
non-activating protease cleavage sites and the black triangle
indicates the activating PAR-2 protease cleavage site); see also
FIG. 4. The present invention includes anti-PAR-2 antibodies that
block the activating PAR-2 protease cleavage site but do not block
one or both of the non-activating protease cleavage sites. Whether
a candidate antibody blocks or does not block a particular protease
cleavage site can be determined by a person of ordinary skill in
the art using any suitable assay such as the exemplary in vitro
blocking assays set forth in Example 8 herein. As illustrated in
Example 8, the exemplary antibody H4H581P was shown to block
trypsin cleavage at the activating PAR-2 protease cleavage site and
at the non-activating protease cleavage site located at the
junction of residues Lys-34 and Gly-35 of human PAR-2 (SEQ ID
NO:851), but did not block cleavage at the non-activating protease
cleavage site located at the junction of residues Arg-31 and Ser-32
of human PAR-2 (SEQ ID NO:851). By contrast, the comparator
antibody used in Example 8 blocked cleavage at the activating PAR-2
protease cleavage site and at both non-activating sites. The
differential blocking capabilities of these exemplary anti-PAR-2
antibodies most likely reflects differences in the particular
regions of the PAR-2 molecule with which these antibodies bind
(see, e.g., Example 9 herein).
As used herein, an antibody "does not bind" to a specified target
molecule (e.g., mouse PAR-2, rat PAR-2, rabbit PAR-2, dog PAR-2,
pig PAR-2, or fragment thereof) if the antibody, when tested for
binding to the target molecule at 25.degree. C. in a surface
plasmon resonance assay, exhibits a K.sub.D of greater than 500 nM,
or if tested for binding to the target molecule at 25.degree. C. in
an enzyme-linked immunosorbent assay (ELISA) exhibits an EC.sub.50
of greater than 50 nM, or fails to exhibit any binding in either
type of assay or equivalent thereof.
Certain anti-PAR-2 antibodies of the present invention are able to
inhibit or attenuate PAR-2 activation in an in vitro cellular
assay. A non-limiting, exemplary in vitro cellular assay for PAR-2
activation is illustrated in Example 6, herein. In this Example,
cells are used which express PAR-2 and harbor a construct
comprising NF-.kappa.B fused to a reporter molecule (e.g.,
luciferase). Briefly, such cells are combined with an anti-PAR-2
antibody, followed by treatment with a PAR-2 protease. Cells that
are treated with the protease in the presence of an inhibitory
anti-PAR-2 antibody will exhibit significantly less or no reporter
signal as compared to cells treated with the protease in the
absence of an inhibitory anti-PAR-2 antibody. The concentration of
antibody necessary to achieve half-maximal inhibition of reporter
signal (IC.sub.50) can be calculated using such an assay. The
present invention includes inhibitory anti-PAR-2 antibodies that
exhibit an IC.sub.50 of less than 300 nM when tested in an in vitro
cellular assay for PAR-2 activation as described above. For
example, the invention includes anti-PAR-2 antibodies with an
IC.sub.50 of less than 300, 290, 280, 270, 260, 250, 240, 230, 220,
210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80,
70, 60, 50, 40, 30, 20, 10, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4,
3, 2, or 1 nM when tested in an in vitro cellular assay for PAR-2
activation as described above in which the cells are incubated with
the antibody for 1 h at 37.degree. C. followed by treatment with 20
nM trypsin (or other PAR-2 protease) for 5 h at 37.degree. C.
The present invention includes anti-PAR-2 antibodies and antigen
binding fragments thereof which bind to one or more of the
following peptides: Peptide A (GTNRSSKGRSLIGKVDGT, SEQ ID NO:852);
Peptide B (SLIGKVDGTSHVTG, SEQ ID NO:853); Peptide C (SLIGKV, SEQ
ID NO:854); Peptide D (N-terminal domain of human PAR-2--mouse IgG,
SEQ ID NO:855); Peptide E (LAPGRNNSKGRSLIGRLETQ, SEQ ID NO:856);
Peptide F (GTNRSSKGRSLIGRVDGT, SEQ ID NO:857); Peptide G
(GPNSKGRSLIGRLDTP, SEQ ID NO:858); Peptide H (GTNKTSKGRSLIGRNTGS,
SEQ ID NO:859); Peptide I (GTNRTSKGRSLIGKTDSS, SEQ ID NO:860);
Peptide J (GTSRPSKGRSLIGKADNT, SEQ ID NO:861); Peptide K
(ATNATLDPRSFLLRNPND, SEQ ID NO:862); Peptide L (DTNNLAKPTLPIKTFRGA,
SEQ ID NO:863); or Peptide M (ESGSTGGGDDSTPSILPAP, SEQ ID NO:864).
Additional information regarding these peptides can be found in
Example 3 herein. These peptides may contain no additional labels
or moieties, or they may contain an N-terminal or C-terminal label
or moiety. In one embodiment, the label or moiety is biotin. In a
binding assay, the location of a label (if any) may determine the
orientation of the peptide relative to the surface upon which the
peptide is bound. For example, if a surface is coated with avidin,
a peptide containing an N-terminal biotin will be oriented such
that the C-terminal portion of the peptide will be distal to the
surface.
With regard to the aforementioned Peptides, the present invention
includes anti-PAR-2 antibodies with one or more of the following
binding profiles: (1) binding to Peptides A and B, but not binding
to Peptide C; (2) binding to Peptides A, B and D, but not binding
to Peptide C; (3) binding to Peptides A, B, D and F, but not
binding to Peptide C; (4) binding to Peptides A, B, D and F, but
not binding to either of Peptides C or E; (5) binding to Peptides
A, B and D, but not binding to any of Peptides K, L or M; (6)
binding to Peptides A, B and F, but not binding to any of Peptides
K, L or M; (7) binding to Peptides A, B, D and F, but not binding
to any of Peptides K, L or M; and/or (8) binding to at least three
of Peptides A, B, C, D, E, F, G, I and J, but not binding to
Peptide H. Other binding profiles of the antibodies of the
invention will be evident from the examples herein.
Epitope Mapping and Related Technologies
To screen for antibodies that bind to a particular epitope (e.g.,
those which block binding of IgE to its high affinity receptor), a
routine cross-blocking assay such as that described Antibodies,
Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., N.Y.)
can be performed. Other methods include alanine scanning mutants,
peptide blots (Reineke, 2004, Methods Mol Biol 248:443-463, herein
specifically incorporated by reference in its entirety), or peptide
cleavage analysis. In addition, methods such as epitope excision,
epitope extraction and chemical modification of antigens can be
employed (Tomer, 2000, Protein Science 9:487-496, herein
specifically incorporated by reference in its entirety).
The term "epitope" refers to a site on an antigen to which B and/or
T cells respond. B-cell epitopes can be formed both from contiguous
amino acids or noncontiguous amino acids juxtaposed by tertiary
folding of a protein. Epitopes formed from contiguous amino acids
are typically retained on exposure to denaturing solvents, whereas
epitopes formed by tertiary folding are typically lost on treatment
with denaturing solvents. An epitope typically includes at least 3,
and more usually, at least 5 or 8-10 amino acids in a unique
spatial conformation.
Modification-Assisted Profiling (MAP), also known as Antigen
Structure-based Antibody Profiling (ASAP) is a method that
categorizes large numbers of monoclonal antibodies (mAbs) directed
against the same antigen according to the similarities of the
binding profile of each antibody to chemically or enzymatically
modified antigen surfaces (US 2004/0101920, herein specifically
incorporated by reference in its entirety). Each category may
reflect a unique epitope either distinctly different from or
partially overlapping with epitope represented by another category.
This technology allows rapid filtering of genetically identical
antibodies, such that characterization can be focused on
genetically distinct antibodies. When applied to hybridoma
screening, MAP may facilitate identification of rare hybridoma
clones that produce mAbs having the desired characteristics. MAP
may be used to sort the anti-PAR-2 antibodies of the invention into
groups of antibodies binding different epitopes.
The present invention includes anti-PAR-2 antibodies which bind to
an epitope at or near (e.g., within 5, 10, 15 or 20 amino acids of)
the activating PAR-2 protease cleavage site. In certain
embodiments, the anti-PAR-2 antibodies bind to an epitope located
upstream from (i.e., N-terminal to) the activating PAR-2 protease
cleavage site. In certain other embodiments of the invention, the
anti-PAR-2 antibodies bind to an epitope located downstream from
(i.e., C-terminal to) the activating PAR-2 protease cleavage site.
In yet other embodiments, the anti-PAR-2 antibodies of the
invention may bind an epitope that includes both amino acid
sequences located upstream from the activating PAR-2 protease
cleavage site and amino acid sequences located downstream from the
activating PAR-2 protease cleavage site.
Alternatively, the anti-PAR-2 antibodies of the invention may, in
certain embodiments, bind to an epitope located on one or more
extracellular loops of the PAR-2 protein (e.g., extracellular loop
1, extracellular loop 2 and/or extracellular loop 3).
The present invention includes isolated human antibodies or
antigen-binding fragments thereof that interact with certain amino
acid residues located downstream from the activating PAR-2 protease
cleavage site. For example, the present invention includes isolated
human antibodies or antigen-binding fragments thereof that interact
with Val-42 and Asp-43 of human PAR-2 (SEQ ID NO:851). In addition
to these two residues, the isolated human antibodies or
antigen-binding fragments thereof may also interact with one or
more of the following residues located downstream from the
activating PAR-2 protease cleavage site: Ser-37, Leu-38, Ile-39,
Gly-40 or Gly-44 of human PAR-2 (SEQ ID NO:851). In certain
embodiments, the isolated human antibody or antigen binding
fragment thereof does not interact with Lys-41 of human PAR-2 (SEQ
ID NO:851). For example, the present invention includes isolated
human antibodies or antigen-binding fragments thereof that interact
with Ser-37, Leu-38, Ile-39, Gly-40, Val-42 and Asp-43 of human
PAR-2 (SEQ ID NO:851), and do not interact with Lys-41 of human
PAR-2 (SEQ ID NO:851). The experimental procedures illustrated in
Example 9 can be used to determine if a candidate anti-PAR-2
antibody "interacts with" or "does not interact with" a particular
amino acid residue of PAR-2. For example, if a candidate antibody
is tested for binding to a peptide having SEQ ID NO:879
(corresponding to the N-terminal region of PAR-2 wherein Val-42 of
PAR-2 is mutated to alanine, see, e.g., Tables 24-28) using the
procedure of Example 9, and the T.sub.1/2 of the antibody is less
than 30% the T.sub.1/2 observed when the candidate antibody is
tested for binding to the wild-type peptide (SEQ ID NO:871), then
for purposes of the present disclosure, the candidate antibody is
deemed to "interact with" the amino acid that was mutated to
alanine (in this case, Val-42); that is, binding of the candidate
antibody is substantially reduced when the amino acid corresponding
to Val-42 is mutated to alanine (such residues are depicted by
black circles in FIG. 5). On the other hand, if a candidate
antibody is tested for binding to a peptide having SEQ ID NO:878
(corresponding to the N-terminal region of PAR-2 wherein Lys-41 of
PAR-2 is mutated to alanine, see, e.g., Tables 24-28) using the
procedure of Example 9, and the T.sub.1/2 of the antibody is
greater than or equal to 30% the T.sub.1/2 observed when the
candidate antibody is tested for binding to the wild-type peptide
(SEQ ID NO:871), then for purposes of the present disclosure, the
candidate antibody is deemed to "not interact with" the amino acid
that was mutated to alanine (in this case, Lys-41); that is,
binding of the candidate antibody is not substantially reduced when
the amino acid corresponding to Lys-41 is mutated to alanine (such
residues are depicted by white circles in FIG. 5).
The present invention includes anti-PAR-2 antibodies that bind to
the same epitope as any of the specific exemplary antibodies
described herein (e.g., H4H581P, H4H588N, H4H591N or H4H618N).
Likewise, the present invention also includes anti-PAR-2 antibodies
that cross-compete for binding to PAR-2 or a PAR-2 fragment with
any of the specific exemplary antibodies described herein (e.g.,
H4H581P, H4H588N, H4H591N or H4H618N).
One can easily determine whether an antibody binds to the same
epitope as, or competes for binding with, a reference anti-PAR-2
antibody by using routine methods known in the art. For example, to
determine if a test antibody binds to the same epitope as a
reference anti-PAR-2 antibody of the invention, the reference
antibody is allowed to bind to a PAR-2 protein or peptide under
saturating conditions. Next, the ability of a test antibody to bind
to the PAR-2 molecule is assessed. If the test antibody is able to
bind to PAR-2 following saturation binding with the reference
anti-PAR-2 antibody, it can be concluded that the test antibody
binds to a different epitope than the reference anti-PAR-2
antibody. On the other hand, if the test antibody is not able to
bind to the PAR-2 molecule following saturation binding with the
reference anti-PAR-2 antibody, then the test antibody may bind to
the same epitope as the epitope bound by the reference anti-PAR-2
antibody of the invention. Additional routine experimentation
(e.g., peptide mutation and binding analyses) can then be carried
out to confirm whether the observed lack of binding of the test
antibody is in fact due to binding to the same epitope as the
reference antibody or if steric blocking (or another phenomenon) is
responsible for the lack of observed binding. Experiments of this
sort can be performed using ELISA, RIA, Biacore, flow cytometry or
any other quantitative or qualitative antibody-binding assay
available in the art. In accordance with certain embodiments of the
present invention, two antibodies bind to the same (or overlapping)
epitope if, e.g., a 1-, 5-, 10-, 20- or 100-fold excess of one
antibody inhibits binding of the other by at least 50% but
preferably 75%, 90% or even 99% as measured in a competitive
binding assay (see, e.g., Junghans et al., Cancer Res.
1990:50:1495-1502). Alternatively, two antibodies are deemed to
bind to the same epitope if essentially all amino acid mutations in
the antigen that reduce or eliminate binding of one antibody reduce
or eliminate binding of the other. Two antibodies are deemed to
have "overlapping epitopes" if only a subset of the amino acid
mutations that reduce or eliminate binding of one antibody reduce
or eliminate binding of the other.
To determine if an antibody competes for binding with a reference
anti-PAR-2 antibody, the above-described binding methodology is
performed in two orientations: In a first orientation, the
reference antibody is allowed to bind to a PAR-2 molecule under
saturating conditions followed by assessment of binding of the test
antibody to the PAR-2 molecule. In a second orientation, the test
antibody is allowed to bind to a PAR-2 molecule under saturating
conditions followed by assessment of binding of the reference
antibody to the PAR-2 molecule. If, in both orientations, only the
first (saturating) antibody is capable of binding to the PAR-2
molecule, then it is concluded that the test antibody and the
reference antibody compete for binding to PAR-2. As will be
appreciated by a person of ordinary skill in the art, an antibody
that competes for binding with a reference antibody may not
necessarily bind to the same epitope as the reference antibody, but
may sterically block binding of the reference antibody by binding
an overlapping or adjacent epitope.
Species Selectivity and Species Cross-Reactivity
According to certain embodiments of the invention, the anti-PAR-2
antibodies bind to human PAR-2 but not to PAR-2 from other species.
Alternatively, the anti-PAR-2 antibodies of the invention, in
certain embodiments, bind to human PAR-2 and to PAR-2 from one or
more non-human species. For example, the anti-PAR-2 antibodies of
the invention may bind to human PAR-2 and may bind or not bind, as
the case may be, to one or more of mouse, rat, guinea pig, hamster,
gerbil, pig, cat, dog, rabbit, goat, sheep, cow, horse, camel,
cynomologous, marmoset, rhesus or chimpanzee PAR-2.
Immunoconjugates
The invention encompasses anti-PAR-2 monoclonal antibodies
conjugated to a therapeutic moiety ("immunoconjugate"), such as a
cytotoxin, a chemotherapeutic drug, an immunosuppressant or a
radioisotope. Cytotoxic agents include any agent that is
detrimental to cells. Examples of suitable cytotoxic agents and
chemotherapeutic agents for forming immunoconjugates are known in
the art, see for example, WO 05/103081, herein specifically
incorporated by reference).
Multispecific Antibodies
The antibodies of the present invention may be monospecific,
bi-specific, or multispecific. Multispecific antibodies may be
specific for different epitopes of one target polypeptide or may
contain antigen-binding domains specific for more than one target
polypeptide. See, e.g., Tutt et al., 1991, J. Immunol. 147:60-69;
Kufer et al., 2004, Trends Biotechnol. 22:238-244. The anti-PAR-2
antibodies of the present invention can be linked to or
co-expressed with another functional molecule, e.g., another
peptide or protein. For example, an antibody or fragment thereof
can be functionally linked (e.g., by chemical coupling, genetic
fusion, noncovalent association or otherwise) to one or more other
molecular entities, such as another antibody or antibody fragment
to produce a bi-specific or a multispecific antibody with a second
binding specificity. For example, the present invention includes
bi-specific antibodies wherein one arm of an immunoglobulin is
specific for human PAR-2 or a fragment thereof, and the other arm
of the immunoglobulin is specific for a second therapeutic target
or is conjugated to a therapeutic moiety such as a trypsin
inhibitor.
An exemplary bi-specific antibody format that can be used in the
context of the present invention involves the use of a first
immunoglobulin (Ig) C.sub.H3 domain and a second Ig C.sub.H3
domain, wherein the first and second Ig C.sub.H3 domains differ
from one another by at least one amino acid, and wherein at least
one amino acid difference reduces binding of the bispecific
antibody to Protein A as compared to a bi-specific antibody lacking
the amino acid difference. In one embodiment, the first Ig C.sub.H3
domain binds Protein A and the second Ig C.sub.H3 domain contains a
mutation that reduces or abolishes Protein A binding such as an
H95R modification (by IMGT exon numbering; H435R by EU numbering).
The second C.sub.H3 may further comprise a Y96F modification (by
IMGT; Y436F by EU). Further modifications that may be found within
the second C.sub.H3 include: D16E, L18M, N44S, K52N, V57M, and V821
(by IMGT; D356E, L358M, N384S, K392N, V397M, and V422I by EU) in
the case of IgG1 antibodies; N44S, K52N, and V82I (IMGT; N384S,
K392N, and V422I by EU) in the case of IgG2 antibodies; and Q15R,
N44S, K52N, V57M, R69K, E79Q, and V82I (by IMGT; Q355R, N384S,
K392N, V397M, R409K, E419Q, and V422I by EU) in the case of IgG4
antibodies. Variations on the bi-specific antibody format described
above are contemplated within the scope of the present
invention.
Therapeutic Formulation and Administration
The invention provides therapeutic compositions comprising the
anti-PAR-2 antibodies or antigen-binding fragments thereof of the
present invention. The administration of therapeutic compositions
in accordance with the invention will be administered with suitable
carriers, excipients, and other agents that are incorporated into
formulations to provide improved transfer, delivery, tolerance, and
the like. A multitude of appropriate formulations can be found in
the formulary known to all pharmaceutical chemists: Remington's
Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. These
formulations include, for example, powders, pastes, ointments,
jellies, waxes, oils, lipids, lipid (cationic or anionic)
containing vesicles (such as LIPOFECTIN.TM.), DNA conjugates,
anhydrous absorption pastes, oil-in-water and water-in-oil
emulsions, emulsions carbowax (polyethylene glycols of various
molecular weights), semi-solid gels, and semi-solid mixtures
containing carbowax. See also Powell et al. "Compendium of
excipients for parenteral formulations" PDA (1998) J Pharm Sci
Technol 52:238-311.
The dose of antibody may vary depending upon the age and the size
of a subject to be administered, target disease, conditions, route
of administration, and the like. The preferred dose is typically
calculated according to body weight or body surface area. When an
antibody of the present invention is used for treating a condition
or disease associated with PAR-2 activity in an adult patient, it
may be advantageous to intravenously administer the antibody of the
present invention normally at a single dose of about 0.01 to about
20 mg/kg body weight, more preferably about 0.02 to about 7, about
0.03 to about 5, or about 0.05 to about 3 mg/kg body weight.
Depending on the severity of the condition, the frequency and the
duration of the treatment can be adjusted. Effective dosages and
schedules for administering PAR-2 antibodies may be determined
empirically; for example, patient progress can be monitored by
periodic assessment, and the dose adjusted accordingly. Moreover,
interspecies scaling of dosages can be performed using well-known
methods in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res.
8:1351).
Various delivery systems are known and can be used to administer
the pharmaceutical composition of the invention, e.g.,
encapsulation in liposomes, microparticles, microcapsules,
recombinant cells capable of expressing the mutant viruses,
receptor mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol.
Chem. 262:4429-4432). Methods of introduction include, but are not
limited to, intradermal, intramuscular, intraperitoneal,
intravenous, subcutaneous, intranasal, epidural, and oral routes.
The composition may be administered by any convenient route, for
example by infusion or bolus injection, by absorption through
epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and
intestinal mucosa, etc.) and may be administered together with
other biologically active agents. Administration can be systemic or
local.
A pharmaceutical composition of the present invention can be
delivered subcutaneously or intravenously with a standard needle
and syringe. In addition, with respect to subcutaneous delivery, a
pen delivery device readily has applications in delivering a
pharmaceutical composition of the present invention. Such a pen
delivery device can be reusable or disposable. A reusable pen
delivery device generally utilizes a replaceable cartridge that
contains a pharmaceutical composition. Once all of the
pharmaceutical composition within the cartridge has been
administered and the cartridge is empty, the empty cartridge can
readily be discarded and replaced with a new cartridge that
contains the pharmaceutical composition. The pen delivery device
can then be reused. In a disposable pen delivery device, there is
no replaceable cartridge. Rather, the disposable pen delivery
device comes prefilled with the pharmaceutical composition held in
a reservoir within the device. Once the reservoir is emptied of the
pharmaceutical composition, the entire device is discarded.
Numerous reusable pen and autoinjector delivery devices have
applications in the subcutaneous delivery of a pharmaceutical
composition of the present invention. Examples include, but are not
limited to AUTOPEN.TM. (Owen Mumford, Inc., Woodstock, UK),
DISETRONIC.TM. pen (Disetronic Medical Systems, Bergdorf,
Switzerland), HUMALOG MIX 75/25.TM. pen, HUMALOG.TM. pen, HUMALIN
70/30.TM. pen (Eli Lilly and Co., Indianapolis, Ind.), NOVOPEN.TM.
I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN
JUNIOR.TM. (Novo Nordisk, Copenhagen, Denmark), BD.TM. pen (Becton
Dickinson, Franklin Lakes, N.J.), OPTIPEN.TM., OPTIPEN PRO.TM.,
OPTIPEN STARLET.TM., and OPTICLIK.TM. (sanofi-aventis, Frankfurt,
Germany), to name only a few. Examples of disposable pen delivery
devices having applications in subcutaneous delivery of a
pharmaceutical composition of the present invention include, but
are not limited to the SOLOSTAR.TM. pen (sanofi-aventis), the
FLEXPEN.TM. (Novo Nordisk), and the KWIKPEN.TM. (Eli Lilly), the
SURECLICK.TM. Autoinjector (Amgen, Thousand Oaks, Calif.), the
PENLET.TM. (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey,
L.P.), and the HUMIRA.TM. Pen (Abbott Labs, Abbott Park Ill.), to
name only a few.
In certain situations, the pharmaceutical composition can be
delivered in a controlled release system. In one embodiment, a pump
may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref.
Biomed. Eng. 14:201). In another embodiment, polymeric materials
can be used; see, Medical Applications of Controlled Release,
Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Fla. In yet
another embodiment, a controlled release system can be placed in
proximity of the composition's target, thus requiring only a
fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical
Applications of Controlled Release, supra, vol. 2, pp. 115-138).
Other controlled release systems are discussed in the review by
Langer, 1990, Science 249:1527-1533.
The injectable preparations may include dosage forms for
intravenous, subcutaneous, intracutaneous and intramuscular
injections, drip infusions, etc. These injectable preparations may
be prepared by methods publicly known. For example, the injectable
preparations may be prepared, e.g., by dissolving, suspending or
emulsifying the antibody or its salt described above in a sterile
aqueous medium or an oily medium conventionally used for
injections. As the aqueous medium for injections, there are, for
example, physiological saline, an isotonic solution containing
glucose and other auxiliary agents, etc., which may be used in
combination with an appropriate solubilizing agent such as an
alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol,
polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80,
HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor
oil)], etc. As the oily medium, there are employed, e.g., sesame
oil, soybean oil, etc., which may be used in combination with a
solubilizing agent such as benzyl benzoate, benzyl alcohol, etc.
The injection thus prepared is preferably filled in an appropriate
ampoule.
Advantageously, the pharmaceutical compositions for oral or
parenteral use described above are prepared into dosage forms in a
unit dose suited to fit a dose of the active ingredients. Such
dosage forms in a unit dose include, for example, tablets, pills,
capsules, injections (ampoules), suppositories, etc. The amount of
the aforesaid antibody contained is generally about 5 to about 500
mg per dosage form in a unit dose; especially in the form of
injection, it is preferred that the aforesaid antibody is contained
in about 5 to about 100 mg and in about 10 to about 250 mg for the
other dosage forms.
Therapeutic Uses of the Antibodies
The antibodies of the invention are useful, inter alia, for the
treatment, prevention and/or amelioration of any disease or
disorder associated with PAR-2 activity, including diseases or
disorders associated with the proteolytic activation of PAR-2.
Exemplary diseases and disorders that can be treated with the
anti-PAR-2 antibodies of the present invention include pain
conditions such as nociceptive pain and visceral pain, as well as
pain associated with conditions such as inflammation,
post-operative incision, neuropathy, bone fracture, burn,
osteoporotic fracture, bone cancer, gout, migraine headache,
fibromyalgia, etc. The antibodies of the invention may also be used
to treat, prevent and/or ameliorate inflammatory conditions such as
joint inflammation, airway inflammation (e.g., asthma), skin
inflammation, dermatitis (e.g., atopic dermatitis, allergic contact
dermatitis, etc.), inflammatory bowel disease (IBD),
glomerulonephritis, interstitial cystitis, bladder inflammation,
hyperalgesia, rheumatoid arthritis, osteoarthritis, inflammatory
arthritis, multiple sclerosis, anti-phospholipid syndrome,
alpha-1-antitrypsin deficiency, etc. The antibodies of the present
invention may be used to treat fibrotic conditions, including,
e.g., scleroderma, biliary cirrhosis, post-transplant fibrosis,
renal fibrosis, lung fibrosis, liver fibrosis, pancreatic fibrosis,
testicular fibrosis, hypertrophic scarring and cutaneous keloids.
In certain embodiments, the antibodies of the invention are useful
for the treatment of gastrointestinal conditions (e.g., celiac
disease, Crohn's disease, ulcerative colitis, idiopathic
gastroparesis, pancreatitis, irritable bowel syndrome (IBS) and
ulcers (including gastric and duodenal ulcers)); acute lung injury;
acute renal injury; and sepsis. The anti-PAR-2 antibodies of the
present invention are also useful for the treatment of pruritus;
e.g., dermal/pruritoceptive, neuropathic, neurogenic, and
psychogenic itch, as well as pruritus associated with atopic
dermatitis, psoriasis, burn scarring (burn-related itch),
hypertrophic scarring, keloids, renal failure and hepatic failure.
Other therapeutic uses of the anti-PAR-2 antibodies of the present
invention include the treatment, prevention and/or amelioration of
Alzheimer's disease, Netherton's disease, pathological
angiogenesis, chronic urticaria, angioedema, mastocytosis,
endometriosis, infertility (e.g., male infertility associated with
testicular fibrosis), mast cell-mediated diseases, Clostridium
difficile Toxin-A induced enteritis, and cancer (e.g., blood cell
cancer, brain cancer, breast cancer, colon cancer, head and neck
cancer, liver cancer, lung cancer, ovarian cancer, pancreatic
cancer, prostate cancer, skin cancer, stomach cancer, etc.).
Combination Therapies
The present invention includes therapeutic administration regimens
which comprise administering an anti-PAR-2 antibody of the present
invention in combination with at least one additional
therapeutically active component. Non-limiting examples of such
additional therapeutically active components include other PAR-2
antagonists (e.g., anti-PAR-2 antibody or small molecule inhibitor
of PAR-2 (e.g., N1-3-methylbutyryl-N4-6-aminohexanoyl-piperazine;
ENMD-1068)), cytokine inhibitors (e.g., an interleukin-1 (IL-1)
inhibitor (such as rilonacept or anakinra, a small molecule IL-1
antagonist, or an anti-IL-1 antibody); IL-18 inhibitor (such as a
small molecule IL-18 antagonist or an anti-IL-18 antibody); IL-4
inhibitor (such as a small molecule IL-4 antagonist, an anti-IL-4
antibody or an anti-IL-4 receptor antibody); IL-6 inhibitor (such
as a small molecule IL-6 antagonist, an anti-IL-6 antibody or an
anti-IL-6 receptor antibody); antiepileptic drugs (e.g.,
gabapentain); nerve growth factor (NGF) inhibitors (e.g., a small
molecule NGF antagonist or an anti-NGF antibody); low dose
cochicine; aspirin; NSAIDs; steroids (e.g., prednisone,
methotrexate, etc.); low dose cyclosporine A; tumor necrosis factor
(TNF) or TNF receptor inhibitors (e.g., a small molecule TNF or
TNFR antagonist or an anti-TNF or TNFR antibody); uric acid
synthesis inhibitors (e.g., allopurinol); uric acid excretion
promoters (e.g., probenecid, sulfinpyrazone, benzbromarone, etc.);
other inflammatory inhibitors (e.g., inhibitors of caspase-1, p38,
IKK1/2, CTLA-4Ig, etc.); and/or corticosteroids. The additional
therapeutically active component(s) may be administered prior to,
concurrent with, or after the administration of the anti-PAR-2
antibody of the present invention.
Diagnostic Uses of the Antibodies
The anti-PAR-2 antibodies of the present invention may also be used
to detect and/or measure PAR-2 in a sample, e.g., for diagnostic
purposes. For example, an anti-PAR-2 antibody, or fragment thereof,
may be used to diagnose a condition or disease characterized by
aberrant expression (e.g., over-expression, under-expression, lack
of expression, etc.) of PAR-2. Exemplary diagnostic assays for
PAR-2 may comprise, e.g., contacting a sample, obtained from a
patient, with an anti-PAR-2 antibody of the invention, wherein the
anti-PAR-2 antibody is labeled with a detectable label or reporter
molecule. Alternatively, an unlabeled anti-PAR-2 antibody can be
used in diagnostic applications in combination with a secondary
antibody which is itself detectably labeled. The detectable label
or reporter molecule can be a radioisotope, such as .sup.3H,
.sup.14H, .sup.32P, .sup.35S, or .sup.125I; a fluorescent or
chemiluminescent moiety such as fluorescein isothiocyanate, or
rhodamine; or an enzyme such as alkaline phosphatase,
.beta.-galactosidase, horseradish peroxidase, or luciferase.
Specific exemplary assays that can be used to detect or measure
PAR-2 in a sample include enzyme-linked immunosorbent assay
(ELISA), radioimmunoassay (RIA), and fluorescence-activated cell
sorting (FACS).
Samples that can be used in PAR-2 diagnostic assays according to
the present invention include any tissue or fluid sample obtainable
from a patient which contains detectable quantities of PAR-2
protein, or fragments thereof, under normal or pathological
conditions. Generally, levels of PAR-2 in a particular sample
obtained from a healthy patient (e.g., a patient not afflicted with
a disease or condition associated with abnormal PAR-2 levels or
activity) will be measured to initially establish a baseline, or
standard, level of PAR-2. This baseline level of PAR-2 can then be
compared against the levels of PAR-2 measured in samples obtained
from individuals suspected of having a PAR-2 related disease or
condition.
EXAMPLES
The following examples are put forth so as to provide those of
ordinary skill in the art with a complete disclosure and
description of how to make and use the methods and compositions of
the invention, and are not intended to limit the scope of what the
inventors regard as their invention. Efforts have been made to
ensure accuracy with respect to numbers used (e.g., amounts,
temperature, etc.) but some experimental errors and deviations
should be accounted for. Unless indicated otherwise, parts are
parts by weight, molecular weight is average molecular weight,
temperature is in degrees Centigrade, and pressure is at or near
atmospheric.
Example 1
Generation of Human Antibodies to Human PAR-2
An immunogen comprising human PAR-2 peptide having the amino acid
sequence GTNRSSKGRSLIGKVDGT (SEQ ID NO:852) was administered
directly, with an adjuvant to stimulate the immune response, to a
VELOCIMMUNE.RTM. mouse comprising DNA encoding human Immunoglobulin
heavy and kappa light chain variable regions. The antibody immune
response was monitored by a PAR-2-specific immunoassay. When a
desired immune response was achieved splenocytes were harvested and
fused with mouse myeloma cells to preserve their viability and form
hybridoma cell lines. The hybridoma cell lines were screened and
selected to identify cell lines that produce PAR-2-specific
antibodies. Using this technique several anti-PAR-2 chimeric
antibodies (i.e., antibodies possessing human variable domains and
mouse constant domains) were obtained; exemplary antibodies
generated in this manner were designated as follows: H2M588,
H2M589, H1M590, H2M591, H1M592, H1M595, H2M609, H2M610, H2M611,
H1M612, H1M613, H2M614, H1M615, H1M616, H3M617, H2M618, H1M619, and
H3M620.
Anti-PAR-2 antibodies were also isolated directly from
antigen-positive B cells without fusion to myeloma cells, as
described in U.S. 2007/0280945A1, herein specifically incorporated
by reference in its entirety. Using this method, several fully
human anti-PAR-2 antibodies (i.e., antibodies possessing human
variable domains and human constant domains) were obtained;
exemplary antibodies generated in this manner were designated as
follows: H1H571, H1H572, H1H573, H1H574, H1H575, H1H576, H1H577,
H1H578, H1H579, H1H580, H1H581, H1H583, H1H584, H1H585, H1H586, and
H1H587.
The biological properties of the exemplary anti-PAR-2 antibodies
generated in accordance with the methods of this Example are
described in detail in the Examples set forth below.
Example 2
Heavy and Light Chain Variable Region Amino Acid Sequences
Table 1 sets forth the heavy and light chain variable region amino
acid sequence pairs of selected anti-PAR-2 antibodies and their
corresponding antibody identifiers. The N, P and G designations
refer to antibodies having heavy and light chains with identical
CDR sequences but with sequence variations in regions that fall
outside of the CDR sequences (i.e., in the framework regions).
Thus, N, P and G variants of a particular antibody have identical
CDR sequences within their heavy and light chain variable regions
but differ from one another within their framework regions.
TABLE-US-00001 TABLE 1 HCVR/LCVR HCVR/LCVR HCVR/LCVR Name SEQ ID
NOs Name SEQ ID NOs Name SEQ ID NOs H1H571N 458/466 H1H571P 474/476
H1H571G 478/480 H1H572N 482/490 H1H572P 498/500 H1H572G 502/504
H1H573N 506/514 H1H573P 522/524 H1H573G 526/528 H1H574N 530/538
H1H574P 546/548 H1H574G 550/552 H1H575N 554/562 H1H575P 570/572
H1H575G 574/576 H1H576N 578/586 H1H576P 594/596 H1H576G 598/600
H1H577N 602/610 H1H577P 618/620 H1H577G 622/624 H1H578N 626/634
H1H578P 642/644 H1H578G 646/648 H1H579N 650/658 H1H579P 666/668
H1H579G 670/672 H1H580N 674/682 H1H580P 690/692 H1H580G 694/696
H1H581N 698/706 H1H581P 714/692 H1H581G 718/720 H1H583N 722/730
H1H583P 738/740 H1H583G 742/744 H1H584N 746/754 H1H584P 762/764
H1H584G 766/768 H1H585N 770/778 H1H585P 786/788 H1H585G 790/792
H1H586N 794/802 H1H586P 810/812 H1H586G 814/816 H1H587N 818/826
H1H587P 834/836 H1H587G 838/840 H2M588N 98/106 H2M588P 114/116
H2M588G 118/120 H2M589N 122/130 H2M589P 138/140 H2M589G 142/144
H1M590N 218/226 H1M590P 234/236 H1M590G 238/240 H2M591N 146/154
H2M591P 162/164 H2M591G 166/168 H1M592N 242/250 H1M592P 258/260
H1M592G 262/264 H1M595N 266/274 H1M595P 282/284 H1M595G 286/288
H2M609N 170/178 H2M609P 186/188 H2M609G 190/192 H2M610N 194/202
H2M610P 210/212 H2M610G 214/216 H2M611N 290/298 H2M611P 306/308
H2M611G 310/312 H1M612N 2/10 H1M612P 18/20 H1M612G 22/24 H1M613N
410/418 H1M613P 426/428 H1M613G 430/432 H2M614N 314/322 H2M614P
330/332 H2M614G 334/336 H1M615N 26/34 H1M615P 42/44 H1M615G 46/48
H1M616N 50/58 H1M616P 66/68 H1M616G 70/72 H3M617N 362/370 H3M617P
378/380 H3M617G 382/384 H2M618N 338/346 H2M618P 354/356 H2M618G
358/360 H1M619N 74/82 H1M619P 90/92 H1M619G 94/96 H3M620N 386/394
H3M620P 402/404 H3M620G 406/408 FP3B12F6N 434/442 FP3B12F6P 450/452
FP3B12F6G 454/456
Example 3
Antibody Binding to PAR-2 Peptides
Synthetic peptides (Celtek Bioscience, Nashville, Tenn.) of PAR-2
and PAR-2 related sequences were generated to characterize the
binding profiles of anti-PAR-2 antibodies. Both biotinylated and
unbiotinylated forms for the various peptides were generated for
the examples set forth below. For biotinylated forms, biotin
moieties were covalently attached to the peptide at either the
C-terminus or the N-terminus via a G.sub.4S linker. Table 2 sets
forth the sequence and derivation of these peptides.
TABLE-US-00002 TABLE 2 SEQ Designation Species Gene Sequence ID NO:
Peptide A Human PAR-2 GTNRSSKGRSLIGKVDGT 852 Peptide B Human PAR-2
SLIGKVDGTSHVTG 853 Peptide C Human PAR-2 SLIGKV 854 Peptide D Human
PAR-2 SLIGKVDGTSHVTGKGVTVE 855 TVFSVDEFSASVLTGKLTTVF LP-mouse IgG2a
Peptide E Mouse (Mus musculus) PAR-2 LAPGRNNSKGRSLIGRLETQ 856
Peptide F Monkey (Macaca mulatta) PAR-2 GTNRSSKGRSLIGRVDGT 857
Peptide G Rat (Rattus norvegicus) PAR-2 GPNSKGRSLIGRLDTP 858
Peptide H Rabbit (Oryctolagus PAR-2 GTNKTSKGRSLIGRNTGS 859
cuniculus) Peptide I Dog (Canis familiaris) PAR-2
GTNRTSKGRSLIGKTDSS 860 Peptide J Pig (Sus scrofa) PAR-2
GTSRPSKGRSLIGKADNT 861 Peptide K Human PAR-1 ATNATLDPRSFLLRNPND 862
Peptide L Human PAR-3 DTNNLAKPTLPIKTFRGA 863 Peptide M Human PAR-4
ESGSTGGGDDSTPSILPAP 864
Anti-PAR-2 antibodies were tested for their ability to bind to the
PAR-2 peptides. Various PAR-2 Peptides (Table 3) were coated onto
96-well plates at a concentration of 2 .mu.g/ml and incubated
overnight followed by blocking in a suitable blocking agent for one
hour. In a similar fashion, for biotinylated peptides (N-Term:
N-terminal biotinylated; C-Term: C-terminal biotinylated), avidin
was coated on plates at 2 .mu.g/ml followed by incubation with
biotinylated PAR-2 peptides at a concentration of 0.2 .mu.g/ml and
incubated for one hour. Purified anti-PAR-2 antibodies were added
to the plate coated with PAR-2 peptides to a final concentration
ranging from 0.2 to 2.0 .mu.g/ml and incubated for one hour at room
temperature. Detection of bound antibodies was determined with
Horse-Radish Peroxidase (HRP) conjugated anti-mouse or human IgG
(Jackson Immuno Research Lab, West Grove, Pa.) and developed by
standard colorimetric response using tetramethylbenzidine (TMB)
substrate. Absorbance was read at OD.sub.450 for 0.1 second.
Relative binding (+++, ++, +) to unbiotinylated (No Biotin) or
biotinylated Peptides A, B and C as compared to no binding (-) for
each anti-PAR-2 antibody tested according to the observed
OD.sub.450 value (1.0-4.0, 0.50-0.99, 0.1-0.49, 0.0-0.09,
respectively) is shown in Table 3. Control: "Sam11," a commercially
available mouse monoclonal antibody that binds human PAR-2 (Santa
Cruz Biotechnology, Santa Cruz, Calif.).
TABLE-US-00003 TABLE 3 Peptide A Peptide B Peptide C No N- C- No N-
C- N- C- Antibody Biotin Term Term Biotin Term Term Term Term
H2M588N +++ +++ +++ +++ +++ +++ - - H2M589N +++ +++ +++ +++ +++ +++
- - H1M590N +++ +++ +++ - - - - - H2M591N +++ +++ +++ +++ +++ +++ -
- H1M592N +++ +++ +++ - ++ +++ +++ +++ H1M595N +++ +++ +++ - - - ++
- H2M609N +++ +++ +++ - - - - - H2M610N +++ +++ +++ - - - - -
H2M611N +++ +++ +++ +++ +++ +++ - - H1M612N +++ +++ +++ - - - - -
H1M613N +++ +++ +++ - ++ +++ +++ +++ H2M614N ++ +++ +++ - - - - -
H1M615N +++ +++ +++ - - - - - H1M616N +++ +++ +++ - - - - - H2M618N
+++ +++ +++ +++ +++ +++ - - H1M619N +++ +++ +++ - - - - - H3M620N
+++ ++ +++ - - - - - Control - - - +++ +++ +++ - -
In a similar experiment, selected anti-PAR-2 antibodies cloned onto
a mutant human IgG4 (SEQ ID NO:849) were tested for their ability
to bind unbiotinylated and biotinylated forms of human PAR-2
peptides (as described above). Results are shown in Table 4.
TABLE-US-00004 TABLE 4 Peptide A Peptide B Peptide C No N- C- No N-
C- N- C- Antibody Biotin Term Term Biotin Term Term Term Term
H4H572P - - - - - - - - H4H573P +++ +++ +++ - - - - - H4H576P + - -
- - - - - H4H578P +++ +++ +++ - - - - - H4H579P +++ +++ +++ +++ +++
+++ - - H4H580P +++ +++ +++ +++ +++ +++ - - H4H581P +++ +++ +++ +++
+++ +++ ++ + H4H583P +++ +++ +++ - - - - - H4H584P +++ +++ +++ +++
+++ +++ - - H4H585P +++ +++ +++ +++ +++ +++ + + H4H587P - - - - - -
- + H4H588N +++ +++ +++ +++ +++ +++ - - H4H591N +++ +++ +++ +++ +++
+++ - - H4H618N +++ +++ +++ +++ +++ +++ - - Control - - - +++ +++
+++ - -
In another experiment, selected anti-PAR-2 antibodies were tested
for binding to unbiotinylated Peptides D, K, L and M (as described
above). Results for chimeric antibodies (e.g. H2M588N) and fully
human antibodies (e.g. H4H572P) are shown in Tables 5 and 6,
respectively. For Peptide D, detection of bound antibodies was
determined with Horse-Radish Peroxidase (HRP) conjugated anti-mouse
.kappa. (Southern Biotech, Birmingham, Ala.).
TABLE-US-00005 TABLE 5 Antibody Peptide D Peptide K Peptide L
Peptide M H2M588N +++ - - - H2M589N +++ - - - H1M590N - - - -
H2M591N +++ - - - H1M592N + - - - H1M595N - - - - H2M609N + - - -
H2M610N - - - - H2M611N + - - - H1M612N - - - - H1M613N + - - -
H2M614N - - - - H1M615N - - - - H1M616N - - - - H2M618N +++ - - -
H1M619N - - - - H3M620N - - - - Control +++ - - -
TABLE-US-00006 TABLE 6 Antibody Peptide D Peptide K Peptide L
Peptide M H4H572P + - - - H4H573P + - - - H4H576P + - - - H4H578P +
- - - H4H579P +++ - - - H4H580P +++ - - - H4H581P +++ + + + H4H583P
++ - - - H4H584P +++ - - - H4H585P +++ + + + H4H587P + - - -
H4H588N +++ - - - H4H591N +++ + + + H4H618N +++ - - - Control +++ -
- -
In another experiment, selected anti-PAR-2 antibodies were tested
for binding to N-terminal biotinylated mouse (Peptide E N-Term) and
monkey (Peptide F N-Term) PAR-2 peptides (as described above).
TABLE-US-00007 TABLE 7 Antibody Peptide E N-Term Peptide F N-Term
H2M588N - +++ H2M589N - +++ H1M590N +++ +++ H2M591N - +++ H1M592N -
- H1M595N +++ +++ H2M609N +++ +++ H2M610N +++ +++ H2M611N - +++
H1M612N +++ +++ H1M613N - - H2M614N +++ +++ H1M615N +++ +++ H1M616N
+++ +++ H2M618N - +++ H1M619N +++ +++ H3M620N +++ ++ Control -
-
In another experiment, selected anti-PAR-2 antibodies cloned onto
human IgG4 were tested for binding to unbiotinylated and
biotinylated forms of Peptides E through J (as described above).
Results are shown in Table 8.
TABLE-US-00008 TABLE 8 Peptide E Peptide G No N- Peptide F No N- C-
Antibody Biotin Term N-Term Biotin Term Term Peptide H Peptide I
Peptide J H4H572P + - - - - + - - - H4H573P +++ +++ +++ +++ +++ ++
+++ +++ +++ H4H576P + - - - - + - - - H4H578P +++ +++ +++ +++ +++ +
+++ +++ +++ H4H579P +++ +++ +++ +++ +++ +++ + +++ + H4H580P +++ +++
+++ +++ +++ +++ - +++ + H4H581P +++ +++ +++ +++ +++ +++ - +++ +++
H4H583P +++ +++ +++ +++ +++ +++ +++ +++ +++ H4H584P +++ +++ +++ +++
+++ +++ - +++ ++ H4H585P +++ +++ +++ +++ +++ +++ + +++ +++ H4H587P
- - - - + - - - + H4H588N - - +++ - + - - - - H4H591N + + +++ + + +
+ - + H4H618N - - +++ - - - - - - Control - - - - - - - - -
In another experiment, selected anti-PAR-2 antibodies cloned onto
human IgG4 were tested for binding to unbiotinylated and
biotinylated forms of PAR-2 peptides (Peptides A, E, F and G; as
described above). In this experiment, anti-PAR-2 antibodies,
serially diluted three-fold from 13.3 nM to 0.22 pM, were incubated
on the peptide-coated plates for one hour at room temperature.
Absorbance values at 450 nm were analyzed using a sigmoidal
dose-response model in GraphPad Prism (GraphPad Software, Inc., La
Jolla, Calif.) and EC.sub.50 values were reported (Table 9).
EC.sub.50 values are defined as the antibody concentration required
to achieve 50% maximal binding to PAR-2 peptide.
TABLE-US-00009 TABLE 9 EC.sub.50 (nM) Peptide A Peptide E Peptide G
No No Peptide F No Antibody Biotin C-Term N-Term Biotin N-Term
N-Term Biotin C-Term N-Term H4H572P >50 >50 >50 >50
>50 >50 >50 >50 >50 H4H573P 0.093 0.022 0.093 0.355
0.016 0.018 0.014 10.130 0.017 H4H576P >50 >50 >50 >50
>50 >50 >50 >50 >50 H4H578P 0.034 0.040 0.062 2.778
0.090 0.036 0.046 >50 0.081 H4H579P 0.038 0.076 0.077 0.713
0.540 0.061 0.055 0.044 0.059 H4H580P 0.090 0.202 0.160 2.533 0.932
0.148 0.139 0.100 0.142 H4H581P 0.012 0.028 0.020 0.029 0.032 0.020
0.020 0.013 0.019 H4H583P 0.008 0.018 0.015 0.019 0.014 0.013 0.012
0.630 0.015 H4H584P 0.012 0.015 0.019 2.152 0.511 0.012 0.013 0.015
0.012 H4H585P 0.017 0.021 0.026 0.308 0.189 0.017 0.018 0.021 0.017
H4H587P >50 >50 >50 >50 >50 >50 >50 >50
>50 H4H588N 0.010 0.016 0.019 >50 >50 0.012 >50 >50
>50 H4H591N 0.010 0.016 0.022 >50 >50 0.011 >50 >50
>50 H4H618N 0.009 0.016 0.021 >50 >50 0.011 >50 >50
>50 Control >50 >50 >50 >50 >50 >50 >50
>50 >50
As indicated by the foregoing experiments, antibodies H4H581P,
H4H588N, H4H591N or H4H618N all show substantial binding to human
Peptides A, B and D, which comprise the sequence SLIGKVDGT (amino
acids 10-18 of SEQ ID NO:852), as well as to monkey Peptide F,
which comprises the sequence SLIGRVDGT (amino acids 10-18 of SEQ ID
NO:857). For antibodies H4H588N, H4H591N and H4H618N, the sequence
VDGT, located downstream from the activating PAR-2 protease
cleavage site, appears to be particularly important for binding
since changes to this sequence resulted in substantially reduced or
no binding by these antibodies (see, e.g., binding data for
Peptides E (mouse), G (rat), H (rabbit), I (dog) and J (pig)).
Example 4
Antigen Binding Affinity Determination
Equilibrium dissociation constants (K.sub.D values) for antigen
binding to selected purified PAR-2 antibodies were determined by
surface kinetics using a real-time surface plasmon resonance
biosensor assay. Antibody was captured on either a rabbit
anti-mouse IgG polyclonal antibody (GE Healthcare, Piscataway,
N.J.) surface or a goat anti-human IgG polyclonal antibody (Jackson
Immuno Research Lab, West Grove, Pa.) surface created through
direct amine chemical coupling to a BIACORE.TM. CM5 sensor chip to
form a captured antibody surface. Various concentrations (ranging
from 15.6 to 250 nM) of monomeric human PAR-2 peptides (Peptides A
and B) were injected at a rate of 1000 .mu.l/min over the captured
antibody surface for 90 seconds. Antigen-antibody binding and
dissociation were monitored in real time at room temperature.
Kinetic analysis was performed to calculate K.sub.D and half-life
of antigen/antibody complex dissociation (Table 10). For those
antibodies where no T.sub.1/2 value is shown, steady state analysis
was used to calculate the K.sub.D value. NB: no binding observed
under current experimental conditions. ND: not determined.
TABLE-US-00010 TABLE 10 Peptide A Peptide B Antibody K.sub.D (nM)
T.sub.1/2 (min) K.sub.D (nM) T.sub.1/2 (min) H4H572P NB -- ND --
H4H573P 749 -- ND -- H4H576P NB -- ND -- H4H578P 245 0.17 ND --
H4H579P 15 4 >500 -- H4H580P 103 0.88 ND -- H4H581P 9.44 1.4
>500 -- H4H583P 37.1 0.37 NB -- H4H584P 22 0.73 >500 --
H4H585P 8.78 3.7 >500 -- H4H587P NB -- ND -- H1M590N 173 -- ND
-- H1M592N 2100 -- ND -- H1M595N 510 -- ND -- H1M612N 180 -- ND --
H1M613N 2100 -- ND -- H1M615N 162 -- ND -- H1M616N 144 -- ND --
H1M619N 164 -- ND -- H2M588N 4.47 60.8 61.7 7.7 H2M589N 3.75 51.3
128 7.3 H2M591N 4.22 42.7 151 8.1 H2M610N 71.3 -- 360 0.8 H2M611N
72.8 4.1 1090 1.2 H2M614N 470 -- ND -- H2M618N 9.62 6.7 126 3.5
Control NB -- 149 0.1
In a similar experiment, K.sub.D values for binding to
unbiotinylated monomeric mouse (Peptide E) and N-terminal
biotinylated monkey (Peptide F N-Term) PAR-2 peptides of selected
antibodies cloned onto human IgG4 were determined (as described
above) (Table 11). Antibodies H4H588N, H4H591N, and H4H618N did not
bind Peptide E, while the Control antibody did not bind to either
Peptide E or F.
TABLE-US-00011 TABLE 11 Peptide F N-Term Antibody K.sub.D (nM)
T.sub.1/2 (min) H4H588N 7.10 24 H4H591N 8.54 21 H4H618N 13.8 5
In another series of experiments, equilibrium dissociation
constants (K.sub.D values) for purified antibody binding to
selected biotinylated and unbiotinylated forms of PAR-2 peptides
were determined by surface kinetics using a real-time surface
plasmon resonance biosensor assay. Neutravidin (Pierce, Rockford,
Ill.) was covalently coupled to the surface of a Biacore.TM. C1
chip or CM5 chip using amine coupling chemistry. Biotinylated
(N-Term or C-Term) PAR-2 peptides (Peptides A and B) were
immobilized on the surface via the high affinity binding
interaction between biotin and the amine coupled Neutravidin.
In a first experiment using this format, varying concentrations
(ranging from 5 to 100 .mu.g/ml) of purified antibody were injected
at a rate of 50 .mu.l/min over a surface coated with immobilized
peptide at low-density (<1RU) for 300 seconds. Antibody-peptide
binding and dissociation was monitored in real time 25.degree. C.
(Table 12).
TABLE-US-00012 TABLE 12 Peptide A C-Term Peptide B C-Term Antibody
K.sub.D (nM) T.sub.1/2 (min) K.sub.D (nM) T.sub.1/2 (min) H2M588N
0.826 169 1.49 140 H1M590N 1.27 13 NB -- H2M591N 0.545 209 1.82 94
H2M618N 1.8 79 2.32 60 Control NB -- 0.99 19
In another similar experiment, K.sub.D values for binding to a
low-density surface (<1RU) of biotinylated forms of Peptides A,
B, C, E, F and G of selected antibodies cloned onto human IgG4 were
determined (as described above). Results for binding to C-terminal
and N-terminal biotinylated PAR-2 peptides are shown in Tables
13-14, respectively. In this experiment, only antibody H4H581P
demonstrated affinity for N-terminal biotinylated Peptide C
(K.sub.D of >100 nM), while all other antibodies tested,
including the control, showed no binding to this peptide.
TABLE-US-00013 TABLE 13 Peptide A C-Term Peptide B C-Term Antibody
K.sub.D (nM) T.sub.1/2 (min) K.sub.D (nM) T.sub.1/2 (min) H4H579P
0.143 479 0.453 96 H4H581P 0.237 134 0.346 49 H4H583P 0.898 34 NB
-- H4H584P 0.688 55 1.66 15 H4H585P 0.151 493 0.376 123 H4H588N
0.517 141 1.03 70 H4H590N 3.56 3 NB -- Control NB -- 0.935 14
TABLE-US-00014 TABLE 14 Peptide A Peptide B Peptide E Peptide F
Peptide G N-Term N-Term N-Term N-Term N-Term K.sub.D T.sub.1/2
K.sub.D T.sub.1/2 K.sub.D T.sub.1/2 K.sub.D T.sub.1/2 K- .sub.D
T.sub.1/2 Antibody (nM) (min) (nM) (min) (nM) (min) (nM) (min) (nM)
(min) H4H579P 1.61 46 5.44 55 3.40 20 0.796 70 1.16 38 H4H581P
0.498 41 2.72 38 1.13 21 0.272 78 0.354 62 H4H583P 0.412 46 NB --
1.68 11 0.291 73 1.49 13 H4H584P 0.525 43 3.20 30 >100 -- 0.565
40 1.39 15 H4H585P 1.69 48 5.41 63 >100 -- 0.899 66 1.36 35
H4H588N 1.05 189 0.0272 >1155 NB -- 1.81 94 NB -- H4H590N 1.52 3
NB -- 1.28 7 1.84 2 2.94 2 Control NB -- 0.279 32 NB -- NB -- NB
--
In a similar experiment, K.sub.D values for binding to monomeric
biotinylated and unbiotinylated forms of PAR-2 peptides (Peptides
A, B, E-M) for selected antibodies cloned onto human IgG4 were
determined (as described above for the captured antibody surface).
Results are shown in Tables 15-16. None of the antibodies tested
showed binding to Peptides K, L or M.
TABLE-US-00015 TABLE 15 Peptide B Peptide E Peptide A K.sub.D
K.sub.D Antibody K.sub.D (nM) T.sub.1/2 (min) (nM) T.sub.1/2 (min)
(nM) T.sub.1/2 (min) H4H579P 15 4.1 >500 -- >500 -- H4H581P
9.44 1.4 >500 -- >500 -- H4H583P 37.1 0.37 NB -- >500 --
H4H584P 22 0.73 NB -- NB -- H4H585P 8.78 3.7 >500 -- >500 --
H4H588N 4.95 25.1 84 9 NB -- H4H590N >500 -- NB -- >500 --
Control ND -- 149 0.1 ND --
TABLE-US-00016 TABLE 16 Peptide F N-Term Peptide G Peptide H
Peptide I Peptide J K.sub.D T.sub.1/2 K.sub.D T.sub.1/2 K.sub.D
T.sub.1/2 K.sub.D T.sub.1/2 K- .sub.D Antibody (nM) (min) (nM)
(min) (nM) (min) (nM) (min) (nM) T.sub.1/2 (min) H4H579P 49.4 2 134
0.45 NB -- 311 0.26 NB -- H4H581P 36.6 0.53 40.2 0.63 NB -- 143
0.07 NB -- H4H583P 112 0.47 530 0.07 189 0.17 320 0.16 190 0.16
H4H584P 93.3 0.23 246 0.13 NB -- >500 -- NB -- H4H585P 46.2 2
162 0.33 NB -- 372 0.19 NB -- H4H588N 10.8 20 NB -- NB -- NB -- NB
-- H4H590N >500 -- >500 -- >500 -- >500 -- >500
--
Example 5
Antibody Binding to Cells Engineered to Express PAR-2
To further characterize anti-PAR-2 antibodies, cells of the human
embryonic kidney 293 cell line (HEK293) were genetically engineered
to overexpress either full length human (SEQ ID NO:851) or mouse
(SEQ ID NO:866) PAR-2.
HEK293 cells were transfected with an
NF-.kappa.B-luciferase-IRES-eGFP reporter plasmid. Stability of
transfected cells was demonstrated by response to IL-1.beta. as
detected by eGFP expression through flow cytometry and luciferase
activity. A clonal cell line, named D9, having low background
levels of luciferase activity and high levels of eGFP when induced
with IL-1.beta. was made by a series of successive sorts of cell
populations using flow cytometry. The 293/D9 cell line was then
separately transfected with human PAR-2 or mouse PAR-2 to create
the stable cell lines 293/D9/hPAR-2rec and 293/D9/mPAR-2rec,
respectively.
Binding of anti-PAR-2 antibodies to 293/D9/hPAR-2rec cells was
determined by ELISA. 293/D9 and 293/D9/hPAR-2rec cells were plated
at a density of 5.times.10.sup.4 cells/well in media and incubated
overnight at 37.degree. C. and 5% CO.sub.2. Purified antibody was
added to the cells to a final concentration of 10 .mu.g/ml and
incubated at room temperature for one hour. Cells were then fixed
and washed before detection of bound antibodies with HRP conjugated
anti-mouse IgG and developed by standard colorimetric response
using TMB substrate. Absorbance was read at OD.sub.450 for 0.1
second. The A.sub.450 ratio of antibody binding to 293/D9/hPAR-2rec
cells compared to 293/D9 cells is shown in Table 17.
TABLE-US-00017 TABLE 17 Antibody A.sub.450 ratio H2M588N 2.50
H2M589N 2.03 H1M590N 1.81 H2M591N 2.25 H1M592N 1.25 H1M595N 1.80
H2M609N 1.54 H2M610N 1.66 H2M611N 1.76 H1M612N 1.90 H1M613N 1.27
H2M614N 1.17 H1M615N 2.18 H1M616N 2.78 H2M618N 2.44 H1M619N 1.51
H3M620N 1.24 Control 1.49
In a similar experiment, anti-PAR-2 antibodies were tested for
binding to 293/D9, 293/D9/hPAR-2rec and 293/D9/mPAR-2rec cells
using electro-chemiluminescence technology (Meso Scale Discovery,
MSD, Gaithersburg, Md.). Cells were plated on MSD high-bind 96 well
plates at a density of 4.times.10.sup.4 cells/well in PBS and
incubated for one hour at room temperature. Cells were then blocked
in PBS with 2% BSA and incubated at room temperature for one hour.
Anti-PAR-2 antibodies (ranging from 100 nM to 0.098 nM) were
serially diluted two-fold in PBS with 0.5% BSA and incubated with
the cells for one hour at room temperature followed by washing in
PBS with 0.5% BSA. Sulfo-tagged anti-human IgG antibody (MSD) at a
concentration of 0.1 .mu.g/ml was then added to the cell/antibody
mixture and incubated at room temperature for an additional hour.
After another wash, a 1.times. non-surfactant containing read
buffer was added and electro-chemiluminescent signal was read on
the MSD Sector Imager. Signal of antibody binding to 293/D9 cells
was subtracted from signal to 293/D9/hPAR-2rec or 293/D9/mPAR-2rec
cells. Subtracted data were analyzed using a sigmoidal
dose-response model in GraphPad Prism and EC.sub.50 and B.sub.max
values were reported (Table 18). EC.sub.50 values are defined as
the antibody concentration required to achieve 50% maximal binding
(B.sub.max) to cells.
TABLE-US-00018 TABLE 18 293/D9/hPAR-2rec 293/D9/mPAR-2rec Antibody
EC.sub.50 (nM) B.sub.max (MSD Unit) EC.sub.50 (nM) B.sub.max (MSD
Unit) H4H579P 1.86 25049 NB -- H4H580P 8.69 30177 NB -- H4H581P
0.652 28224 NB -- H4H583P 2.12 13252 9.28 7219 H4H584P 1.45 26044
NB -- H4H585P 1.95 22540 NB -- H4H588N 5.95 27549 NB -- H4H590N
9.72 6554 5.76 13255
Example 6
In Vitro Blocking of Human PAR-2 Activation by Anti-PAR-2
Antibodies
Blocking of PAR-2 activation (signaling) was determined by binding
of selected purified anti-PAR-2 antibodies to 293/D9/hPAR-2rec
cells (see Example 5) by a luciferase assay. 293/D9/hPAR-2rec cells
were plated at a concentration ranging from 5.times.10.sup.4 to
10.sup.5 cells/well in a 96 well plate in low serum media and
incubated overnight at 37.degree. C. with 5% CO.sub.2. The media
was removed and purified anti-PAR-2 antibodies were added to the
cells at various concentrations (ranging from 51 pM to 1 .mu.M) and
incubated for one hour at 37.degree. C. with 5% CO.sub.2. Various
concentrations of different serine proteases (Trypsin, Human
Trypsin 1, Factor Xa and Lung Tryptase) were then added separately
to the cell/antibody mixture and incubated for five hours at
37.degree. C. with 5% CO.sub.2. Proteolytic cleavage of PAR-2 in
this assay leads to expression of the NF-.kappa.B-luciferase
reporter construct, whereas a reduced or attenuated level of
luciferase signal indicates inhibition of PAR-2 cleavage. IC.sub.50
values are shown in Table 19. ND: not determined.
TABLE-US-00019 TABLE 19 IC.sub.50 (nM) 10 nM 200 nM 750 nM Trypsin
Human Factor Lung Antibody 250 nM 75 nM 30 nM 20 nM 10 nM Trypsin 1
Xa Tryptase H2M588N 2.3 5.7 33.0 26.8 10.4 164.9 45.3 1.0 H2M589N
6.3 3.7 ND ND ND ND ND ND H1M591N 4.5 ND ND 121.8 24.2 149.6 51.5
88.1 H2M618N 6.6 7.8 ND 70 12.4 153.5 54.2 7.0
As shown in Table 20, antibodies H4H581P, H4H588N, H4H591N and
H4H618N were able to significantly block protease activation of
PAR-2 in reporter cells. By contrast, anti-PAR-2 antibodies
H4H592N, H4H595N, H4H611N, H4H613N, H4H614N, H4H615N, H4H616N,
H4H617N and H4H619N did not demonstrate any measurable blocking of
PAR-2 cleavage/activation in this assay (data not shown).
TABLE-US-00020 TABLE 20 20 nM Trypsin Antibody IC.sub.50 (nM)
H4H579P 4.1 H4H580P 3.5 H4H581P 1.1 H4H583P 14 H4H584P 5.6 H4H585P
8.9 H4H588N 16.9 H4H591N 204.1 H4H618N 50.2
Under the experimental conditions used in this Example, no blocking
of PAR-2 signaling was observed for antibodies H4H572P, H4H573P,
H4H576P, H4H578P or H4H587P, whereas significant blockage (to
varying degrees) was observed with antibodies H4H579P, H4H580P,
H4H581P, H4H583P, H4H584P, H4H585P, H4H588N, H4H591N and
H4H618N.
In another similar experiment, antibody blocking of PAR-2 signaling
mediated by human Trypsin 1, Factor Xa and Lung Tryptase was
determined for selected purified anti-PAR-2 antibodies cloned onto
human IgG4 (as described above). Results are shown in Table 21.
TABLE-US-00021 TABLE 21 IC.sub.50 (nM) 10 nM Human 200 nM 750 nM
Lung Antibody Trypsin 1 Factor Xa Tryptase H4H581P 7.4 5.3 1.1
H4H588N 42.7 17.1 1.6 H4H591N 104.7 74.6 62.9 H4H618N 92.2 47.2
8.5
HEK293/NF.kappa.B-luciferase cells expressing human, monkey, mouse
or rat PAR-2 were treated with various proteases after
preincubation with increasing amounts of anti-PAR-2 antibody
H4H581P, and the IC.sub.50 was determined. Results are summarized
in Table 22.
TABLE-US-00022 TABLE 22 PAR-2 H4H581P Activator (6 h) Species
EC.sub.50 (nM) IC.sub.50 (nm) Human Pancreatic Human 0.8 1.9
Trypsin mouse 1.4 491.0 monkey 2.4 5.4 rat 6.0 700.0 Human
Kallikrein 5 Human 28.0 0.9 mouse ND ND monkey 16.8 11 Human
Kallikrein 14 Human 5.0 1.2 mouse 8.0 256.0 monkey 6.3 11.6 Bovine
Factor Xa Human 27.2 2.5 mouse 46.3 340.4 monkey 58.2 0.9 Human
Factor Xa Human 46.3 1.1 mouse 78.7 109 monkey ND ND Tryptase Human
61.1 3.5 mouse ND ND monkey ND ND
Under the particular experimental conditions used, the H4H581P
antibody effectively inhibited protease-activation of human and
monkey PAR-2, but not mouse or rat PAR-2.
Example 7
In Vitro Antibody Blocking of Human PAR-2 Dependent Calcium
Mobilization
Blocking of trypsin-stimulated PAR-2 activation (signaling) was
determined by treating HEK293 cells with selected purified
anti-PAR-2 antibodies cloned onto human IgG4 in a calcium
mobilization FLIPR assay (Molecular Devices, Sunnyvale, Calif.).
Also tested in this assay was a non-PAR-2 specific control
antibody.
Briefly, 8.times.10.sup.4 HEK293 cells were plated on Poly-D-Lysine
plates (BD Biosciences, San Jose, Calif.) in low serum media (DME
with 0.5% FBS) and incubated overnight at 37.degree. C. with 5%
CO.sub.2. The following day cells were incubated with various
concentrations (ranging from 0 to 1 .mu.M) of selected anti-PAR-2
antibodies, or a control antibody, followed by the addition of
trypsin. Trypsin-mediated activation of PAR-2 is indicated by
calcium mobilization. In-cell measurement of calcium signaling was
measured using a Fluo-4 NW Calcium Assay Kit (Invitrogen, Carlsbad,
Calif.) on a FlexStation 3 (Molecular Devices, Sunnyvale, Calif.).
The antibody concentration necessary to cause half-maximal
inhibition of trypsin-mediated calcium signaling (IC.sub.50) was
measured for each experimental and control antibody. Results are
shown in Table 23 as IC.sub.50 (nM).
TABLE-US-00023 TABLE 23 Antibody 100 nM Trypsin H4H581P 54.96
H4H588N 29.47 Non-Specific Control >1000
As shown in this Example, antibodies H4H581P and H4H588N each
inhibited trypsin-stimulated calcium signaling to a significant
extent as compared to the control antibody.
Example 8
In Vitro Blocking of Trypsin-Mediated Cleavage of PAR-2
Peptides
A Matrix Assisted Laser Desorption Ionization--Time of Flight
(MALDI-TOF) assay was developed to determine the ability of
selected purified anti-PAR-2 antibodies to block Trypsin-mediated
cleavage of human PAR-2 peptide (Peptide A, SEQ ID NO:852).
Biotinylated versions of Peptide A (containing C-terminal or
N-terminal biotin) were mixed with anti-PAR-2 antibody to achieve a
3:1 molar ratio of antibody to peptide, and then trypsin was added
to the peptide-antibody mixture. Biotinlyated peptides were
recovered by immuno-precipitation (IP) via mono-avidin and analyzed
by MALDI-TOF.
In a typical experiment, selected purified anti-PAR-2 antibodies
cloned onto human IgG4 (H4H581P and H4H588N) were tested for their
ability to block Trypsin-mediated cleavage of the biotinylated
PAR-2 peptides. A non-PAR-2-specific antibody of the same isotype
was used as a negative control ("Neg Ctrl" in FIG. 3). For H4H581P
and the negative control antibody, biotinylated peptides were used
at a final concentration of 4.75 .mu.M and antibodies were used at
14.25 .mu.M. For H4H588N, biotinylated peptides were used at a
final concentration of 2.45 .mu.M and the antibody at 7.35 .mu.M.
Peptide and antibody were mixed in PBS and allowed to come to
equilibrium for 1 hr at room temperature. Trypsin (96 ng) was then
added and the mixture incubated at 37.degree. C. for 0, 5, 10 and
15 minutes. At each time point an aliquot equaling 100 ng of
biotinylated peptide was removed and mixed with 10 .mu.l of
monomeric avidin resin (Pierce) for 1 minute. The bound peptides
were rinsed 3.times. with 200 .mu.l of PBS and then eluted with 20
.mu.l of 100 mM glycine pH 2.5. Salt was removed from the eluted
peptide mixture using ZipTips (Millipore). The molecular weights of
the major biotinylated PAR-2 peptides produced after trypsin
cleavage, as revealed by MALDI-TOF analysis, are summarized in FIG.
3.
The PAR-2 peptides used in these experiments contain two R/S
protease cleavage sites. The first site (designated site "(1)" in
FIG. 3) is an "upstream" cleavage site located N-terminal to the
activating PAR-2 protease cleavage site. The activating PAR-2
protease cleavage site (designated site "(2)" in FIG. 3) is the
site which, when cleaved, results in the formation of the PAR-2
tethered ligand in the naturally occurring protein. The sizes of
the peptides detected following cleavage at the different sites are
shown in the top portion of FIG. 3 (panel A).
As indicated in FIG. 3 (panel B), the C-terminal biotin PAR-2
peptide, when treated with the isotype-matched control antibody,
followed by trypsin incubation, produced a cleavage fragment of
1558 Da (containing residues 10-18 of SEQ ID NO:852). The 1558 Da
fragment is the result of cleavage at the activating PAR-2 protease
cleavage site (2). This cleavage pattern was also observed in the
experiment using the H4H588N anti-PAR-2 antibody. Thus, according
to this assay, neither the control antibody nor the H4H588N
antibody inhibit trypsin cleavage at the activating PAR-2 protease
cleavage site (2).
By contrast, the C-terminal biotin PAR-2 peptide, when treated with
the H4H581P antibody, followed by trypsin incubation, produced a
cleavage fragment of 2073 Da (containing residues 5-18 of SEQ ID
NO:852). The 2073 Da fragment is the fragment produced by cleavage
at the upstream cleavage site (1) only. Thus, cleavage at the
activating PAR-2 protease cleavage site (2) was apparently blocked
by the H4H581P antibody.
Experiments with the N-terminal biotin PAR-2 peptide showed trypsin
cleavage at the upstream cleavage site (1) and thus produced a 988
Da N-biotinylated fragment (containing residues 1-4 of SEQ ID
NO:852) in the presence of all antibodies tested. Therefore, none
of the antibodies tested blocked cleavage at the upstream cleavage
site (1) under these experimental conditions.
As shown in Examples 6 and 7 above, both H4H581P and H4H588N
blocked PAR-2 activation by trypsin in cell-based assays. In the
present Example, however, only H4H581P blocked trypsin cleavage at
the activating PAR-2 protease cleavage site. Without being bound by
any mechanistic theory, it therefore appears that H4H588N may exert
its inhibitory effect(s) by interfering with the interaction
between the tethered ligand and one or more extracellular loops
(e.g., loop 1, loop 2 and/or loop 3) of PAR-2. On the other hand,
H4H581P may inhibit PAR-2 activity primarily by blocking protease
cleavage but may also interfere with tethered ligand interactions
as well.
To further investigate the protease cleavage-blocking properties of
anti-PAR-2 antibodies, additional MALDI-TOF experiments were
conducted using C-terminal biotinylated mouse, rat and human PAR-2
peptides. (See FIG. 4). The antibodies tested in these experiments
were H4H581P, H4H588N, a comparator antibody having the heavy and
light chain variable regions of the antibody referred to as "1A1"
in WO 2009/005726 (referred to in FIG. 4 as "Comp. Ab"), and a
negative control antibody (referred to in FIG. 4 as "Neg Ctrl").
The same experimental procedures that were used in the previous
MALD-TOF experiment (described above) were used in this experiment
as well.
The peptides used in these experiments each possess multiple sites
capable of being cleaved by trypsin (designated "(1)," "(2)," and
"(3)" in FIG. 5.) Site (3) for each peptide is the activating
protease cleavage site. The sizes of the peptides produced
following cleavage at the different sites are shown in the top
portion (panel A) of FIG. 4.
As summarized in FIG. 4, the biotinylated human PAR-2 peptide,
after being treated with H4H581P, and following trypsin incubation,
produced a 2074 kDa peptide which corresponds to cleavage at site
(1) only. Thus, H4H581P blocks cleavage at both site (2) and at
site (3). By contrast, the human PAR-2 peptide, after being treated
with the comparator antibody, and following trypsin incubation,
remained at 2502 kDa which signifies no cleavage. Thus, the
comparator antibody blocks all three protease cleavage sites in
this assay, including the N-terminal-most site (1). When
pre-treated with antibody H4H588N, the human PAR-2 peptide produces
both a 1772 kDa and a 1558 kDa fragment following trypsin cleavage.
This cleavage pattern suggests that H4H588N partially blocks
cleavage at the activating site (3) but completely blocks the
middle site (2).
This experiment was also conducted using a comparator antibody
having the heavy and light chain variable regions of the antibody
referred to as Sam-11 (Molino et al., Arterioscler. Thromb. Vasc.
Biol. 18:825-832 (1998)). As expected, this particular comparator
antibody did not block cleavage at any of the protease cleavage
sites (data not shown).
Example 9
Epitope Mapping by Alanine Scanning Mutagenesis of PAR-2
Peptide
In order to more particularly identify the amino acids of PAR-2
with which the PAR-2 antibodies interact, an alanine scanning study
was carried out using peptides comprising the activating PAR-2
protease cleavage site. For these experiments, 11 separate
C-terminal biotinylated peptides were synthesized in which each
amino acid from position 35 through 45 of human PAR-2 (SEQ ID
NO:851) was individually replaced with an alanine (SEQ ID NOs:
871-882). An additional set of C-terminal biotinylated peptides was
also used which comprise the 14 amino acids located immediately
C-terminal to the activating PAR-2 protease cleavage site, with
Val-42 and/or Asp-43 changed to alanine (SEQ ID NOs: 884-887).
The ability of each peptide mutant to bind to PAR-2 antibodies was
measured using biolayer interferometry (Octet Red; ForteBio). Each
peptide (2.5 .mu.g/ml) was captured on streptavidin coated
biosensor tips (Octet SA sensor) for 10 seconds. To measure binding
and dissociation between each peptide and PAR-2 antibody, the
peptide-coated biosensors were contacted with 200 nM solutions of
PAR-2 antibodies for 5 minutes (binding) followed by transfer to
buffer with no antibody for 10 min (dissociation). The binding of
PAR-2 antibody to each peptide was expressed as percent native
signal after dividing individual antibody binding signals by the
original peptide loading signal observed for that peptide, to
correct for slight variations in peptide loading on the individual
biosensors. Dissociation half-lives (T.sub.1/2) were calculated
from the dissociation curves using the Scrubber version 2.0a
curve-fitting software, and relative half-lives were calculated by
dividing observed half-lives for an individual peptide by the
half-life of the native peptide. The results are expressed as
percent binding and percent T.sub.1/2 relative to WT peptide
(Tables 24-28). [Comparator 1=an antibody having the heavy and
light chain variable regions of the antibody referred to as "1A1"
in WO 2009/005726; Comparator 2=an antibody having the heavy and
light chain variable regions of the antibody referred to as Sam-11
(Molino et al., Arterioscler. Thromb. Vasc. Biol. 18:825-832
(1998)); and Comparator 3=an antibody having the heavy and light
chain variable regions of the antibody referred to as "PAR-B" in US
2010/0119506]. In certain cases, the binding experiments were
repeated (indicated under the column headings Exp1 and Exp2). NB=no
binding observed.
TABLE-US-00024 TABLE 24 H4H581P SEQ ID % Rel Binding % Rel
T.sub.1/2 NO: SEQUENCE Exp1 Exp2 Exp1 Exp2 871
GTNRSSKGRSLIGKVDGT------GGGGSK-B 100 100 100 100 872
GTNRSSKARSLIGKVDGT------GGGGSK-B 78 97 118 117 873
GTNRSSKGASLIGKVDGT------GGGGSK-B 87 105 122 90 874
GTNRSSKGRALIGKVDGT------GGGGSK-B 45 56 7 3 875
GTNRSSKGRSAIGKVDGT------GGGGSK-B 9 19 0.4 0 876
GTNRSSKGRSLAGKVDGT------GGGGSK-B 8 14 0.2 0 877
GTNRSSKGRSLIAKVDGT------GGGGSK-B 101 92 33 15 878
GTNRSSKGRSLIGAVDGT------GGGGSK-B 113 109 63 49 879
GTNRSSKGRSLIGKADGT------GGGGSK-B 36 46 1 1 880
GTNRSSKGRSLIGKVAGT------GGGGSK-B 18 5 36 4 881
GTNRSSKGRSLIGKVDAT------GGGGSK-B 67 102 117 124 882
GTNRSSKGRSLIGKVDGA------GGGGSK-B 65 91 129 94 884
SLIGKVDGTSHVTG-GGGGSK-B -- 100 -- 100 885 SLIGKADGTSHVTG-GGGGSK-B
-- 19 -- 0 886 SLIGKVAGTSHVTG-GGGGSK-B -- NB -- NB 887
SLIGKAAGTSHVTG-GGGGSK-B -- NB -- NB
TABLE-US-00025 TABLE 25 H4H588N SEQ ID % Rel Binding % Rel
T.sub.1/2 NO: SEQUENCE Exp1 Exp2 Exp1 Exp2 871
GTNRSSKGRSLIGKVDGT------GGGGSK-B 100 100 100 100 872
GTNRSSKARSLIGKVDGT------GGGGSK-B 122 99 100 253 873
GTNRSSKGASLIGKVDGT------GGGGSK-B 208 115 100 180 874
GTNRSSKGRALIGKVDGT------GGGGSK-B 119 93 100 70 875
GTNRSSKGRSAIGKVDGT------GGGGSK-B 127 105 100 42 876
GTNRSSKGRSLAGKVDGT------GGGGSK-B 92 85 36 8 877
GTNRSSKGRSLIAKVDGT------GGGGSK-B 30 30 1 0 878
GTNRSSKGRSLIGAVDGT------GGGGSK-B 217 121 108 60 879
GTNRSSKGRSLIGKADGT------GGGGSK-B 74 52 1 0 880
GTNRSSKGRSLIGKVAGT------GGGGSK-B 35 8 4 5 881
GTNRSSKGRSLIGKVDAT------GGGGSK-B 81 67 1 1 882
GTNRSSKGRSLIGKVDGA------GGGGSK-B 125 121 94 33 884
SLIGKVDGTSHVTG-GGGGSK-B -- 100 -- 100 885 SLIGKADGTSHVTG-GGGGSK-B
-- 83 -- 0 886 SLIGKVAGTSHVTG-GGGGSK-B -- NB -- NB 887
SLIGKAAGTSHVTG-GGGGSK-B -- NB -- NB
TABLE-US-00026 TABLE 26 Comparator 1 SEQ ID % Rel Binding % Rel
T.sub.1/2 NO: SEQUENCE Exp1 Exp2 Exp1 Exp2 871
GTNRSSKGRSLIGKVDGT------GGGGSK-B 100 100 100 100 872
GTNRSSKARSLIGKVDGT------GGGGSK-B 111 111 29 27 873
GTNRSSKGASLIGKVDGT------GGGGSK-B 135 87 0.2 0 874
GTNRSSKGRALIGKVDGT------GGGGSK-B 126 102 223 148 875
GTNRSSKGRSAIGKVDGT------GGGGSK-B 147 105 2 1 876
GTNRSSKGRSLAGKVDGT------GGGGSK-B 156 108 47 41 877
GTNRSSKGRSLIAKVDGT------GGGGSK-B 139 108 31 24 878
GTNRSSKGRSLIGAVDGT------GGGGSK-B 118 84 3 2 879
GTNRSSKGRSLIGKADGT------GGGGSK-B 148 104 173 100 880
GTNRSSKGRSLIGKVAGT------GGGGSK-B 124 102 192 111 881
GTNRSSKGRSLIGKVDAT------GGGGSK-B 119 97 130 121 882
GTNRSSKGRSLIGKVDGA------GGGGSK-B 132 119 154 116 884
SLIGKVDGTSHVTG-GGGGSK-B -- NB -- NB 885 SLIGKADGTSHVTG-GGGGSK-B --
NB -- NB 886 SLIGKVAGTSHVTG-GGGGSK-B -- NB -- NB 887
SLIGKAAGTSHVTG-GGGGSK-B -- NB -- NB
TABLE-US-00027 TABLE 27 Comparator 2 SEQ ID % Rel Binding % Rel
T.sub.1/2 NO: SEQUENCE Exp1 Exp2 Exp1 Exp2 871
GTNRSSKGRSLIGKVDGT------GGGGSK-B -- NB -- NB 872
GTNRSSKARSLIGKVDGT------GGGGSK-B -- NB -- NB 873
GTNRSSKGASLIGKVDGT------GGGGSK-B -- NB -- NB 874
GTNRSSKGRALIGKVDGT------GGGGSK-B -- NB -- NB 875
GTNRSSKGRSAIGKVDGT------GGGGSK-B -- NB -- NB 876
GTNRSSKGRSLAGKVDGT------GGGGSK-B -- NB -- NB 877
GTNRSSKGRSLIAKVDGT------GGGGSK-B -- NB -- NB 878
GTNRSSKGRSLIGAVDGT------GGGGSK-B -- NB -- NB 879
GTNRSSKGRSLIGKADGT------GGGGSK-B -- NB -- NB 880
GTNRSSKGRSLIGKVAGT------GGGGSK-B -- NB -- NB 881
GTNRSSKGRSLIGKVDAT------GGGGSK-B -- NB -- NB 882
GTNRSSKGRSLIGKVDGA------GGGGSK-B -- NB -- NB 884
SLIGKVDGTSHVTG-GGGGSK-B -- 100 -- 100 885 SLIGKADGTSHVTG-GGGGSK-B
-- 120 -- 159 886 SLIGKVAGTSHVTG-GGGGSK-B -- 88 -- 27 887
SLIGKAAGTSHVTG-GGGGSK-B -- 87 -- 27
TABLE-US-00028 TABLE 28 Comparator 3 SEQ ID % Rel Binding % Rel
T.sub.1/2 NO: SEQUENCE Exp1 Exp2 Exp1 Exp2 871
GTNRSSKGRSLIGKVDGT------GGGGSK-B -- 100 -- 100 872
GTNRSSKARSLIGKVDGT------GGGGSK-B -- 101 -- 109 873
GTNRSSKGASLIGKVDGT------GGGGSK-B -- 98 -- 7 874
GTNRSSKGRALIGKVDGT------GGGGSK-B -- 106 -- 21 875
GTNRSSKGRSAIGKVDGT------GGGGSK-B -- 115 -- 79 876
GTNRSSKGRSLAGKVDGT------GGGGSK-B -- 92 -- 7 877
GTNRSSKGRSLIAKVDGT------GGGGSK-B -- 101 -- 8 878
GTNRSSKGRSLIGAVDGT------GGGGSK-B -- 109 -- 95 879
GTNRSSKGRSLIGKADGT------GGGGSK-B -- 96 -- 98 880
GTNRSSKGRSLIGKVAGT------GGGGSK-B -- 99 -- 120 881
GTNRSSKGRSLIGKVDAT------GGGGSK-B -- 93 -- 128 882
GTNRSSKGRSLIGKVDGA------GGGGSK-B -- 117 -- 118 884
SLIGKVDGTSHVTG-GGGGSK-B -- NB -- NB 885 SLIGKADGTSHVTG-GGGGSK-B --
NB -- NB 886 SLIGKVAGTSHVTG-GGGGSK-B -- NB -- NB 887
SLIGKAAGTSHVTG-GGGGSK-B -- NB -- NB
The results from the alanine scanning experiments are summarized in
FIG. 5, where the black circles indicate amino acids of PAR-2
which, when changed to alanine, substantially reduce binding by the
corresponding antibody (La, the T1/2 of antibody binding to the
mutated peptide is less than 30% of the T1/2 of antibody binding to
the wild-type peptide). (Open triangles in FIG. 5 indicate
non-activating upstream protease cleavage sites, and the black
triangle indicates the activating protease cleavage site). As
illustrated in FIG. 5, Comparators 1 and 3 were sensitive to
mutations at residues on both sides of the activating protease
cleavage site. By contrast, antibodies H4H581P and H4H588N are only
sensitive to mutations at residues which are found C-terminal to
the activating protease cleavage site. Thus, the H4H581P binding
site on PAR-2 appears to be shifted by about 2-4 amino acids in the
C-terminal direction relative to binding site of the Comparator 1
and 3 antibodies, and the H4H588N binding site is shifted by about
2-4 amino acids in the C-terminal direction from the H4H581P
binding site. The Comparator 2 antibody only bound to the peptides
comprising the 14 amino acids downstream from the activating PAR-2
protease cleavage site, i.e., SLIGKVDGTSHVTG (residues 1-14 of SEQ
ID NO:884), and was sensitive to mutations at the aspartic acid
residue (Asp-43 of SEQ ID NO:851), but not to mutations at the
valine residue (Val-42 of SEQ ID NO:851).
Significantly, this experiment indicates that antibodies H4H581P
and H4H588N both interact with the first V and D residues located
C-terminal to the activating PAR-2 protease cleavage site (i.e.,
Val-42 and Asp-43 of SEQ ID NO:851), whereas the Comparator 1 and 3
antibodies do not interact with either of these residues, and the
Comparator 2 antibody interacts with Asp-43 but not Val-42. The
shifted binding of H4H581P on PAR-2 as compared to the comparator
antibodies may explain the functional superiority of H4H581P over
the comparator as demonstrated in the following in vivo
examples.
Example 10
Dose Response of Anti-PAR-2 Antibody in Pruritus Models
In this Example, the ability of the anti-PAR-2 antibody H4H581P to
attenuate itch in two different protease-induced pruritus models
was assessed. Transgenic mice expressing human PAR-2
(hPAR2.sup.+/+) were used for all cohorts in these experiments.
Separate cohorts of mice received 150 mg/kg (s.c.) of an isotype
control mAb or 10, 25, 50, 75, 100, and 150 mg/kg (s.c.) of
H4H581P. Twenty-four hours after antibody dosing all cohorts
received 150 .mu.g of porcine trypsin, or 10 .mu.g recombinant
human beta tryptase, (s.c., interscapular), which produced bouts of
scratching behavior for 30 to 60 minutes. A dose-response
relationship was observed in mice receiving H4H581P prior to
trypsin injection, with an estimated ED.sub.50 of 25 mg/kg. The
results of these experiments, expressed in terms of the percent
change in the total number of scratching bouts recorded over a 30
minute period following trypsin administration, or over a 60 minute
period following tryptase administration, are shown in Table 29
(all data are represented as mean.+-.SEM; ND=not determined;
*=p<0.05 compared to the isotype control group).
TABLE-US-00029 TABLE 29 Percent Change in Scratching Bouts Dose of
mAb H4H581P Relative to Control (mg/kg) Trypsin Tryptase 10 9.9
.+-. 23.1 -40.7 .+-. 23.4 25 -26.6 .+-. 11.3 -38.5 .+-. 11.1 50
-31.3 .+-. 13.5 -47.7 .+-. 8.0* 75 -34.9 .+-. 4.7* ND 100 -55.2
.+-. 8.0* -39.6 .+-. 6.9* 150 -42.9 .+-. 9.7* ND
As shown in this Example, mAb H4H581P was able to block
protease-induced pruritus behaviors in a dose dependent manner
using two different protease-induced itch models.
Example 11
Reduction of Pruritus Behaviors by Administration of an Anti-PAR-2
Antibody in a Hapten-Induced Chronic Dermatitis Model
To further assess the ability of the anti-PAR-2 antibody H4H581P to
reduce pruritus behaviors in a physiologically relevant disease
state, a mouse model of chronic dermatitis was used. In this model,
mice received repeated cutaneous applications of the haptenizing
agent, oxazolone. This chronic oxazolone-induced dermatitis model
has been shown to recapitulate many of the clinical, histological,
and immunological hallmarks of atopic dermatitis in humans (Man et
al., 2008, J. Invest. Dermatol. 128(1):79-86).
Mice were sensitized with a single cutaneous application of 1%
oxazolone on the left ear or vehicle (100 mg/kg, s.c.). The mice
then received nine total cutaneous applications (challenges) of
0.6% oxazolone between the scapulae beginning seven days after the
sensitization application. Weekly dosing (3 total) of the H4H581P
anti-PAR2 antibody was initiated 24 hours prior to the first
oxazolone challenge (100 mg/kg, s.c.). This dosing paradigm
significantly reduced pruritus behaviors as measured by reduced
numbers of scratching bouts elicited by the final oxazolone
challenge. All data are represented as mean number of scratching
bouts.+-.SEM for n=6 mice/group; *=p<0.05 by Tukey post-hoc test
as compared to the Oxazolone+IgG control group; #=p<0.05 by
Tukey post-hoc test compared to the Vehicle+IgG control group).
TABLE-US-00030 TABLE 30 Time (minutes) Treatment 0-10 10-20 20-30
30-40 40-50 50-60 Total Vehicle + 0.0 .+-. 0.0 0.8 .+-. 0.6 2.2
.+-. 1.4 3.4 .+-. 1.3 4.8 .+-. 2.0 2.4 .+-. 1.0 13.6 .+-. 4.2 IgG
control Oxazolone + 0.5 .+-. 0.5 11.3 .+-. 3.9 24.8 .+-. 9.7 28.0
.+-. 7.3 21.0 .+-. 7.9 21.3 .+-. 7.3 .sup.#106.8 .+-. 33.2 .sup.
IgG control Oxazolone + 0.2 .+-. 0.2 1.6 .+-. 1.2 *6.0 .+-. 2.4
16.6 .+-. 5.1 18.2 .+-. 4.8 18.0 .+-. 5.5 60.6 .+-. 11.6
H4H581P
Histological analysis showed a significant increase in epidermal
hyperplasia and immune cell infiltrate in the oxazolone-challenged
animals. (Data not shown). No significant differences were observed
in any of these parameters between the H4H581P anti-PAR2 antibody
and the isotype control.
Example 12
Comparison of Pruritus Inhibiting Activities of mAb H4H581P
In this Example, the ability of mAb H4H581P to attenuate itching
bouts in a mouse pruritus model was compared to that of a
comparator anti-PAR-2 mAb (Comparator "1A1" described in WO
2009/005726.
Transgenic mice expressing human PAR-2 (hPAR2.sup.+/+) were divided
into 3 cohorts. Cohort A received 50 mg/kg (s.c.) of an isotype
control mAb, cohort B received 50 mg/kg (s.c.) of H4H581P, and
Cohort C received 50 mg/kg (s.c.) of the comparator anti-PAR-2
antibody. Twenty-four hours after antibody dosing all cohorts
received 150 .mu.g of trypsin (s.c., interscapular), which produced
bouts of scratching behavior for 30 minutes. The percent change in
the number of scratching bouts observed for the treated mice as
compared to control-treated mice is shown in Table 29 (all data are
represented as mean.+-.SEM).
TABLE-US-00031 TABLE 31 (% change in scratching bouts Antibody
Treatment (50 mg/kg) from control) mAb H4H581P -41.1 .+-. 13.5
Comparator mAb -13.9 .+-. 9.9
As shown in this Example, mAb H4H581P was substantially more
effective than the comparator mAb in reducing pruritus behaviors in
the trypsin-induced itch model used herein.
The present invention is not to be limited in scope by the specific
embodiments describe herein. Indeed, various modifications of the
invention in addition to those described herein will become
apparent to those skilled in the art from the foregoing description
and the accompanying figures. Such modifications are intended to
fall within the scope of the appended claims.
SEQUENCE LISTINGS
1
8871348DNAArtificial SequenceSynthetic 1gaagtgcagc tggtggagtc
tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt
cacctttgat gattatgcca tgcactgggt ccggcaagct 120ccagggaagg
gcctagagtg ggtctcaggt attacttgga atagtggtaa catggcctat
180gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa
ctccctgtat 240ctgcaaatga acagtctgag agctgaggac acggccttat
attactgtgc aaaagaaaac 300tgggcctttg actactgggg ccagggaacc
cgggtcatcg tctcctca 3482116PRTArtificial SequenceSynthetic 2Glu Val
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45 Ser Gly Ile Thr Trp Asn Ser Gly Asn Met Ala Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Lys Glu Asn Trp Ala Phe Asp Tyr
Trp Gly Gln Gly Thr Arg Val 100 105 110Ile Val Ser Ser
115324DNAArtificial SequenceSynthetic 3ggattcacct ttgatgatta tgcc
2448PRTArtificial SequenceSynthetic 4Gly Phe Thr Phe Asp Asp Tyr
Ala 1 5524DNAArtificial SequenceSynthetic 5attacttgga atagtggtaa
catg 2468PRTArtificial SequenceSynthetic 6Ile Thr Trp Asn Ser Gly
Asn Met 1 5727DNAArtificial SequenceSynthetic 7gcaaaagaaa
actgggcctt tgactac 2789PRTArtificial SequenceSynthetic 8Ala Lys Glu
Asn Trp Ala Phe Asp Tyr 1 59336DNAArtificial SequenceSynthetic
9gatattgtga tgacccagac tccactctcc tcacctgtca cccttggaca gccggcctcc
60atctcctgca ggtctagtca cagcctcgta cacagtgatg gaaacaccta cttgagttgg
120cttcagcaga ggccaggcca gcctccaaga ctcctaattt ataagatttc
taaccggttc 180tctggggtcc cagacagatt cagtggcagt ggggcaggga
cagatttcac actgaaaatc 240agcagggtgg aagctgagga tgtcggggtt
tatttctgca tgcaagctac acaatttccg 300tacacttttg gccaggggac
caagctggag atcaaa 33610112PRTArtificial SequenceSynthetic 10Asp Ile
Val Met Thr Gln Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10
15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser His Ser Leu Val His Ser
20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln
Pro 35 40 45 Pro Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser
Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe
Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val
Tyr Phe Cys Met Gln Ala 85 90 95Thr Gln Phe Pro Tyr Thr Phe Gly Gln
Gly Thr Lys Leu Glu Ile Lys 100 105 1101133DNAArtificial
SequenceSynthetic 11cacagcctcg tacacagtga tggaaacacc tac
331211PRTArtificial SequenceSynthetic 12His Ser Leu Val His Ser Asp
Gly Asn Thr Tyr 1 5 10139DNAArtificial SequenceSynthetic
13aagatttct 9143PRTArtificial SequenceSynthetic 14Lys Ile Ser
11527DNAArtificial SequenceSynthetic 15atgcaagcta cacaatttcc
gtacact 27169PRTArtificial SequenceSynthetic 16Met Gln Ala Thr Gln
Phe Pro Tyr Thr 1 517348DNAArtificial SequenceSynthetic
17gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc
60tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct
120ccagggaagg gcctagagtg ggtctcaggt attacttgga atagtggtaa
catggcctat 180gcggactctg tgaagggccg attcaccatc tccagagaca
acgccaagaa ctccctgtat 240ctgcaaatga acagtctgag agctgaggac
acggccttat attactgtgc aaaagaaaac 300tgggcctttg actactgggg
ccagggaacc ctggtcaccg tctcctca 34818116PRTArtificial
SequenceSynthetic 18Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Thr Trp Asn Ser
Gly Asn Met Ala Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Lys Glu
Asn Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr
Val Ser Ser 11519336DNAArtificial SequenceSynthetic 19gatattgtga
tgacccagac tccactctcc tcacctgtca cccttggaca gccggcctcc 60atctcctgca
ggtctagtca cagcctcgta cacagtgatg gaaacaccta cttgagttgg
120cttcagcaga ggccaggcca gcctccaaga ctcctaattt ataagatttc
taaccggttc 180tctggggtcc cagacagatt cagtggcagt ggggcaggga
cagatttcac actgaaaatc 240agcagggtgg aagctgagga tgtcggggtt
tatttctgca tgcaagctac acaatttccg 300tacacttttg gccaggggac
caagctggag atcaaa 33620112PRTArtificial SequenceSynthetic 20Asp Ile
Val Met Thr Gln Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10
15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser His Ser Leu Val His Ser
20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln
Pro 35 40 45 Pro Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser
Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe
Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val
Tyr Phe Cys Met Gln Ala 85 90 95Thr Gln Phe Pro Tyr Thr Phe Gly Gln
Gly Thr Lys Leu Glu Ile Lys 100 105 11021348DNAArtificial
SequenceSynthetic 21gaagtgcagc tggtggagtc tgggggaggc ttggtacagc
ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatgcca
tgcactgggt ccggcaagct 120ccagggaagg gcctggagtg ggtctcaggt
attacttgga atagtggtaa catgggctat 180gcggactctg tgaagggccg
attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga
acagtctgag agctgaggac acggccttgt attactgtgc aaaagaaaac
300tgggcctttg actactgggg ccagggaacc ctggtcaccg tctcctca
34822116PRTArtificial SequenceSynthetic 22Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Thr Trp Asn Ser Gly Asn Met Gly Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr
Cys 85 90 95Ala Lys Glu Asn Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr
Leu Val 100 105 110Thr Val Ser Ser 11523337DNAArtificial
SequenceSynthetic 23gatattgtga tgacccagac tccactctcc tcacctgtca
cccttggaca gccggcctcc 60atctcctgca ggtctagtca cagcctcgta cacagtgatg
gaaacaccta cttgagttgg 120cttcagcaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgaaaatc 240agcagggtgg
aagctgagga tgtcggggtt tattactgca tgcaagctac acaatttccg
300tacacttttg gccaggggac caagctggag atcaaac 33724112PRTArtificial
SequenceSynthetic 24Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser Pro
Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser
His Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp Leu
Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr Lys
Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser
Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu
Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln Phe
Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105
11025348DNAArtificial SequenceSynthetic 25gaagtgcagc tggtggagtc
tgggggaggc gtggtccagc ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt
cacctttgat gattatacca tgcactgggt ccggcaagtt 120ccagggaagg
acctgaagtg ggtctcaggt attacttgga atggtggtag aaaagcctat
180gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa
ctccctcttt 240ctgcaaatga acagtctgag agctgaggac acggccttct
attactgtgc aaaagaagat 300gaggcttttg actactgggg ccagggaacc
ctggtcaccg tctcctca 34826116PRTArtificial SequenceSynthetic 26Glu
Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30Thr Met His Trp Val Arg Gln Val Pro Gly Lys Asp Leu Lys Trp
Val 35 40 45 Ser Gly Ile Thr Trp Asn Gly Gly Arg Lys Ala Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
Asn Ser Leu Phe65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Phe Tyr Tyr Cys 85 90 95Ala Lys Glu Asp Glu Ala Phe Asp Tyr
Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser
1152724DNAArtificial SequenceSynthetic 27ggattcacct ttgatgatta tacc
24288PRTArtificial SequenceSynthetic 28Gly Phe Thr Phe Asp Asp Tyr
Thr 1 52924DNAArtificial SequenceSynthetic 29attacttgga atggtggtag
aaaa 24308PRTArtificial SequenceSynthetic 30Ile Thr Trp Asn Gly Gly
Arg Lys 1 53127DNAArtificial SequenceSynthetic 31gcaaaagaag
atgaggcttt tgactac 27329PRTArtificial SequenceSynthetic 32Ala Lys
Glu Asp Glu Ala Phe Asp Tyr 1 533336DNAArtificial SequenceSynthetic
33gatattgtga tgacccagac tccactctcc tcacctgtca cccttggaca gccggcctcc
60atctcctgca ggtctagtca aagcctcgta cacagtgatg gcaacaccta cttgagttgg
120cttcagcaga ggccaggcca gcctccaaga ctcctaattt ataagatttc
taaccggttt 180tttggggtcc cagacagatt cagtggcagt ggggcaggga
cagatttcac actgaaaatc 240agcagggtgg aggctgagga tgtcggcgtt
tattactgca tgcaagcaac acaatttccg 300tacacttttg gccaggggac
caagctggag atcaaa 33634112PRTArtificial SequenceSynthetic 34Asp Ile
Val Met Thr Gln Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10
15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln
Pro 35 40 45 Pro Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Phe
Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe
Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val
Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln Phe Pro Tyr Thr Phe Gly Gln
Gly Thr Lys Leu Glu Ile Lys 100 105 1103533DNAArtificial
SequenceSynthetic 35caaagcctcg tacacagtga tggcaacacc tac
333611PRTArtificial SequenceSynthetic 36Gln Ser Leu Val His Ser Asp
Gly Asn Thr Tyr 1 5 10379DNAArtificial SequenceSynthetic
37aagatttct 9383PRTArtificial SequenceSynthetic 38Lys Ile Ser
13927DNAArtificial SequenceSynthetic 39atgcaagcaa cacaatttcc
gtacact 27409PRTArtificial SequenceSynthetic 40Met Gln Ala Thr Gln
Phe Pro Tyr Thr 1 541348DNAArtificial SequenceSynthetic
41gaagtgcagc tggtggagtc tgggggaggc gtggtccagc ctggcaggtc cctgagactc
60tcctgtgcag cctctggatt cacctttgat gattatacca tgcactgggt ccggcaagtt
120ccagggaagg acctgaagtg ggtctcaggt attacttgga atggtggtag
aaaagcctat 180gcggactctg tgaagggccg attcaccatc tccagagaca
acgccaagaa ctccctcttt 240ctgcaaatga acagtctgag agctgaggac
acggccttct attactgtgc aaaagaagat 300gaggcttttg actactgggg
ccagggaacc ctggtcaccg tctcctca 34842116PRTArtificial
SequenceSynthetic 42Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val
Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
Phe Thr Phe Asp Asp Tyr 20 25 30Thr Met His Trp Val Arg Gln Val Pro
Gly Lys Asp Leu Lys Trp Val 35 40 45 Ser Gly Ile Thr Trp Asn Gly
Gly Arg Lys Ala Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Phe Tyr Tyr Cys 85 90 95Ala Lys Glu
Asp Glu Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr
Val Ser Ser 11543336DNAArtificial SequenceSynthetic 43gatattgtga
tgacccagac tccactctcc tcacctgtca cccttggaca gccggcctcc 60atctcctgca
ggtctagtca aagcctcgta cacagtgatg gcaacaccta cttgagttgg
120cttcagcaga ggccaggcca gcctccaaga ctcctaattt ataagatttc
taaccggttt 180tttggggtcc cagacagatt cagtggcagt ggggcaggga
cagatttcac actgaaaatc 240agcagggtgg aggctgagga tgtcggcgtt
tattactgca tgcaagcaac acaatttccg 300tacacttttg gccaggggac
caagctggag atcaaa 33644112PRTArtificial SequenceSynthetic 44Asp Ile
Val Met Thr Gln Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10
15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln
Pro 35 40 45 Pro Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Phe
Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe
Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val
Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln Phe Pro Tyr Thr Phe Gly Gln
Gly Thr Lys Leu Glu Ile Lys 100 105 11045348DNAArtificial
SequenceSynthetic 45gaagtgcagc tggtggagtc tgggggaggc ttggtacagc
ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatacca
tgcactgggt ccggcaagct 120ccagggaagg gcctggagtg ggtctcaggt
attacttgga atggtggtag aaaaggctat 180gcggactctg tgaagggccg
attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga
acagtctgag agctgaggac acggccttgt attactgtgc aaaagaagat
300gaggcttttg actactgggg ccagggaacc ctggtcaccg tctcctca
34846116PRTArtificial SequenceSynthetic 46Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Thr Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Thr Trp Asn Gly Gly Arg Lys Gly Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr
Cys 85 90 95Ala Lys Glu Asp Glu Ala Phe Asp Tyr Trp Gly Gln Gly Thr
Leu Val 100 105 110Thr Val Ser Ser 11547337DNAArtificial
SequenceSynthetic 47gatattgtga tgacccagac tccactctcc tcacctgtca
cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgta cacagtgatg
gcaacaccta cttgagttgg 120cttcagcaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgaaaatc 240agcagggtgg
aagctgagga tgtcggggtt tattactgca tgcaagcaac acaatttccg
300tacacttttg gccaggggac caagctggag atcaaac 33748112PRTArtificial
SequenceSynthetic 48Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser Pro
Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser
Gln Ser Leu Val His Ser 20
25 30Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln
Pro 35 40 45 Pro Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser
Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe
Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val
Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln Phe Pro Tyr Thr Phe Gly Gln
Gly Thr Lys Leu Glu Ile Lys 100 105 11049348DNAArtificial
SequenceSynthetic 49gaagtgcagt tggtggagtc tgggggaggc ttggcacagc
ctggcaggtc cctgagagtc 60tcctgttcag cctctggatt caattttgat gattatgcca
tgcactgggt ccggcaagct 120ccggggaagg gcctggagtg ggtctcaggt
attagttgga atagtggtag cagaggctat 180gcggactctg tgaagggccg
cttcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga
acagtctgag agctgaggac acggccttgt attactgtgt aaaagagaac
300tgggcctttg aatactgggg ccagggaacc ctggtcaccg tctcctca
34850116PRTArtificial SequenceSynthetic 50Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Ala Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Val
Ser Cys Ser Ala Ser Gly Phe Asn Phe Asp Asp Tyr 20 25 30Ala Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Ser Trp Asn Ser Gly Ser Arg Gly Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr
Cys 85 90 95Val Lys Glu Asn Trp Ala Phe Glu Tyr Trp Gly Gln Gly Thr
Leu Val 100 105 110Thr Val Ser Ser 1155124DNAArtificial
SequenceSynthetic 51ggattcaatt ttgatgatta tgcc 24528PRTArtificial
SequenceSynthetic 52Gly Phe Asn Phe Asp Asp Tyr Ala 1
55324DNAArtificial SequenceSynthetic 53attagttgga atagtggtag caga
24548PRTArtificial SequenceSynthetic 54Ile Ser Trp Asn Ser Gly Ser
Arg 1 55527DNAArtificial SequenceSynthetic 55gtaaaagaga actgggcctt
tgaatac 27569PRTArtificial SequenceSynthetic 56Val Lys Glu Asn Trp
Ala Phe Glu Tyr 1 557336DNAArtificial SequenceSynthetic
57gatattgtga tgacccagac tccactctcc tcacctgtca cccttggaca gccggcctcc
60atctcctgca ggtctagtca tagcctcgta cacagtgatg gaagcaccta cttgagttgg
120cttcagcaga ggccaggcca gcctccaaga ctcctaattt ataaaatttc
taaccgattc 180tctggggtcc cagacagatt cagtggcagt ggggcaggga
cagatttcac actgaaaatc 240agcagggtgg aagctgagga tgtcgggctt
tattactgca tgcaggctac acaatttccg 300tacacttttg gccaggggac
caagctggag atcaaa 33658112PRTArtificial SequenceSynthetic 58Asp Ile
Val Met Thr Gln Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10
15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser His Ser Leu Val His Ser
20 25 30Asp Gly Ser Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln
Pro 35 40 45 Pro Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser
Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe
Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Leu
Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln Phe Pro Tyr Thr Phe Gly Gln
Gly Thr Lys Leu Glu Ile Lys 100 105 1105933DNAArtificial
SequenceSynthetic 59catagcctcg tacacagtga tggaagcacc tac
336011PRTArtificial SequenceSynthetic 60His Ser Leu Val His Ser Asp
Gly Ser Thr Tyr 1 5 10619DNAArtificial SequenceSynthetic
61aaaatttct 9623PRTArtificial SequenceSynthetic 62Lys Ile Ser
16327DNAArtificial SequenceSynthetic 63atgcaggcta cacaatttcc
gtacact 27649PRTArtificial SequenceSynthetic 64Met Gln Ala Thr Gln
Phe Pro Tyr Thr 1 565348DNAArtificial SequenceSynthetic
65gaagtgcagc tggtggagtc tgggggaggc ttggcacagc ctggcaggtc cctgagagtc
60tcctgttcag cctctggatt caattttgat gattatgcca tgcactgggt ccggcaagct
120ccggggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag
cagaggctat 180gcggactctg tgaagggccg cttcaccatc tccagagaca
acgccaagaa ctccctgtat 240ctgcaaatga acagtctgag agctgaggac
acggccttgt attactgtgt aaaagagaac 300tgggcctttg aatactgggg
ccagggaacc ctggtcaccg tctcctca 34866116PRTArtificial
SequenceSynthetic 66Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ala
Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Val Ser Cys Ser Ala Ser Gly
Phe Asn Phe Asp Asp Tyr 20 25 30Ala Met His Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser
Gly Ser Arg Gly Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95Val Lys Glu
Asn Trp Ala Phe Glu Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr
Val Ser Ser 11567336DNAArtificial SequenceSynthetic 67gatattgtga
tgacccagac tccactctcc tcacctgtca cccttggaca gccggcctcc 60atctcctgca
ggtctagtca tagcctcgta cacagtgatg gaagcaccta cttgagttgg
120cttcagcaga ggccaggcca gcctccaaga ctcctaattt ataaaatttc
taaccgattc 180tctggggtcc cagacagatt cagtggcagt ggggcaggga
cagatttcac actgaaaatc 240agcagggtgg aagctgagga tgtcgggctt
tattactgca tgcaggctac acaatttccg 300tacacttttg gccaggggac
caagctggag atcaaa 33668112PRTArtificial SequenceSynthetic 68Asp Ile
Val Met Thr Gln Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10
15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser His Ser Leu Val His Ser
20 25 30Asp Gly Ser Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln
Pro 35 40 45 Pro Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser
Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe
Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Leu
Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln Phe Pro Tyr Thr Phe Gly Gln
Gly Thr Lys Leu Glu Ile Lys 100 105 11069348DNAArtificial
SequenceSynthetic 69gaagtgcagc tggtggagtc tgggggaggc ttggtacagc
ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt caattttgat gattatgcca
tgcactgggt ccggcaagct 120ccagggaagg gcctggagtg ggtctcaggt
attagttgga atagtggtag cagaggctat 180gcggactctg tgaagggccg
attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga
acagtctgag agctgaggac acggccttgt attactgtgt aaaagagaac
300tgggcctttg aatactgggg ccagggaacc ctggtcaccg tctcctca
34870116PRTArtificial SequenceSynthetic 70Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Asn Phe Asp Asp Tyr 20 25 30Ala Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Ser Trp Asn Ser Gly Ser Arg Gly Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr
Cys 85 90 95Val Lys Glu Asn Trp Ala Phe Glu Tyr Trp Gly Gln Gly Thr
Leu Val 100 105 110Thr Val Ser Ser 11571337DNAArtificial
SequenceSynthetic 71gatattgtga tgacccagac tccactctcc tcacctgtca
cccttggaca gccggcctcc 60atctcctgca ggtctagtca tagcctcgta cacagtgatg
gaagcaccta cttgagttgg 120cttcagcaga ggccaggcca gcctccaaga
ctcctaattt ataaaatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgaaaatc 240agcagggtgg
aagctgagga tgtcggggtt tattactgca tgcaggctac acaatttccg
300tacacttttg gccaggggac caagctggag atcaaac 33772112PRTArtificial
SequenceSynthetic 72Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser Pro
Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser
His Ser Leu Val His Ser 20 25 30Asp Gly Ser Thr Tyr Leu Ser Trp Leu
Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr Lys
Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser
Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu
Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln Phe
Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105
11073348DNAArtificial SequenceSynthetic 73gaagtgcagc tggtggagtc
tgggggaggc ttggtacagg ctggcaggtc cctgcgactc 60tcctgtgcag cctctggatt
cacctttgat gattatgcca tgcactgggt ccggcaagct 120ccagggaagg
gcctggagtg ggtctcaggt attagttgga atagtggtag cagaggctat
180gcggactctg tgaagggccg attcaccatc tccagagaca acgccaaaaa
ctccctgcat 240ctgcaaatgt acagtctgag agctgaggac acggccttgt
attactgtgc aaaagagaac 300tggtcctttg actactgggg ccagggaacc
ctggtcaccg tctcctca 34874116PRTArtificial SequenceSynthetic 74Glu
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Arg 1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Arg Gly Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
Asn Ser Leu His65 70 75 80Leu Gln Met Tyr Ser Leu Arg Ala Glu Asp
Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Lys Glu Asn Trp Ser Phe Asp Tyr
Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser
1157524DNAArtificial SequenceSynthetic 75ggattcacct ttgatgatta tgcc
24768PRTArtificial SequenceSynthetic 76Gly Phe Thr Phe Asp Asp Tyr
Ala 1 57724DNAArtificial SequenceSynthetic 77attagttgga atagtggtag
caga 24788PRTArtificial SequenceSynthetic 78Ile Ser Trp Asn Ser Gly
Ser Arg 1 57927DNAArtificial SequenceSynthetic 79gcaaaagaga
actggtcctt tgactac 27809PRTArtificial SequenceSynthetic 80Ala Lys
Glu Asn Trp Ser Phe Asp Tyr 1 581336DNAArtificial SequenceSynthetic
81gatattgtga tgacccagac tccactctcc tcacctgtca cccttggaca gccggcctcc
60atctcctgca ggtctagtca aagcctcgta cacagtgatg gaaacaccta cttgagttgg
120cttcagcaga ggccaggcca gcctccaaga ctcctaattt ataagatttc
ttaccggttc 180tctggggtcc cagacagatt cagtggcagt ggggcaggga
cagatttcac actgaaaatc 240agcagggtgg caactgagga tgtcggggtt
tattactgca tgcaagctac acaattgccg 300tacacttttg gccaggggac
caagctggag atcaaa 33682112PRTArtificial SequenceSynthetic 82Asp Ile
Val Met Thr Gln Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10
15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln
Pro 35 40 45 Pro Arg Leu Leu Ile Tyr Lys Ile Ser Tyr Arg Phe Ser
Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe
Thr Leu Lys Ile65 70 75 80Ser Arg Val Ala Thr Glu Asp Val Gly Val
Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln Leu Pro Tyr Thr Phe Gly Gln
Gly Thr Lys Leu Glu Ile Lys 100 105 1108333DNAArtificial
SequenceSynthetic 83caaagcctcg tacacagtga tggaaacacc tac
338411PRTArtificial SequenceSynthetic 84Gln Ser Leu Val His Ser Asp
Gly Asn Thr Tyr 1 5 10859DNAArtificial SequenceSynthetic
85aagatttct 9863PRTArtificial SequenceSynthetic 86Lys Ile Ser
18727DNAArtificial SequenceSynthetic 87atgcaagcta cacaattgcc
gtacact 27889PRTArtificial SequenceSynthetic 88Met Gln Ala Thr Gln
Leu Pro Tyr Thr 1 589348DNAArtificial SequenceSynthetic
89gaagtgcagc tggtggagtc tgggggaggc ttggtacagg ctggcaggtc cctgcgactc
60tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct
120ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag
cagaggctat 180gcggactctg tgaagggccg attcaccatc tccagagaca
acgccaaaaa ctccctgcat 240ctgcaaatgt acagtctgag agctgaggac
acggccttgt attactgtgc aaaagagaac 300tggtcctttg actactgggg
ccagggaacc ctggtcaccg tctcctca 34890116PRTArtificial
SequenceSynthetic 90Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
Gln Ala Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser
Gly Ser Arg Gly Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ala Lys Asn Ser Leu His65 70 75 80Leu Gln Met Tyr
Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Lys Glu
Asn Trp Ser Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr
Val Ser Ser 11591336DNAArtificial SequenceSynthetic 91gatattgtga
tgacccagac tccactctcc tcacctgtca cccttggaca gccggcctcc 60atctcctgca
ggtctagtca aagcctcgta cacagtgatg gaaacaccta cttgagttgg
120cttcagcaga ggccaggcca gcctccaaga ctcctaattt ataagatttc
ttaccggttc 180tctggggtcc cagacagatt cagtggcagt ggggcaggga
cagatttcac actgaaaatc 240agcagggtgg caactgagga tgtcggggtt
tattactgca tgcaagctac acaattgccg 300tacacttttg gccaggggac
caagctggag atcaaa 33692112PRTArtificial SequenceSynthetic 92Asp Ile
Val Met Thr Gln Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10
15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln
Pro 35 40 45 Pro Arg Leu Leu Ile Tyr Lys Ile Ser Tyr Arg Phe Ser
Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe
Thr Leu Lys Ile65 70 75 80Ser Arg Val Ala Thr Glu Asp Val Gly Val
Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln Leu Pro Tyr Thr Phe Gly Gln
Gly Thr Lys Leu Glu Ile Lys 100 105 11093348DNAArtificial
SequenceSynthetic 93gaagtgcagc tggtggagtc tgggggaggc ttggtacagc
ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatgcca
tgcactgggt ccggcaagct 120ccagggaagg gcctggagtg ggtctcaggt
attagttgga atagtggtag cagaggctat 180gcggactctg tgaagggccg
attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga
acagtctgag agctgaggac acggccttgt attactgtgc aaaagagaac
300tggtcctttg actactgggg ccagggaacc ctggtcaccg tctcctca
34894116PRTArtificial SequenceSynthetic 94Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Ser Trp Asn Ser Gly Ser Arg Gly Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr
Cys 85 90 95Ala Lys Glu Asn Trp Ser Phe Asp Tyr Trp Gly Gln Gly Thr
Leu Val 100 105 110Thr Val Ser Ser 11595337DNAArtificial
SequenceSynthetic 95gatattgtga tgacccagac
tccactctcc tcacctgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca
aagcctcgta cacagtgatg gaaacaccta cttgagttgg 120cttcagcaga
ggccaggcca gcctccaaga ctcctaattt ataagatttc taaccggttc
180tctggggtcc cagacagatt cagtggcagt ggggcaggga cagatttcac
actgaaaatc 240agcagggtgg aagctgagga tgtcggggtt tattactgca
tgcaagctac acaattgccg 300tacacttttg gccaggggac caagctggag atcaaac
33796112PRTArtificial SequenceSynthetic 96Asp Ile Val Met Thr Gln
Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser
Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn
Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro
Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55
60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65
70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln
Ala 85 90 95Thr Gln Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu
Ile Lys 100 105 11097357DNAArtificial SequenceSynthetic
97gaggtgcagc tgttggagtc tgggggaggc ttggtacagc cgggggggtc cctgagactc
60tcctgtgcag cctctggatt cacctttagc agctatgcca tgacctgggt ccgccaggct
120ccggggaagg ggctgtattg ggtctcagct attagtggtg gtcgtggtag
cgcatactac 180gcagactccg tgaagggccg gttcaccatc tccagagaca
attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg agccgaggac
acggccgtat attactgtgc gaaagagggg 300gatagtggct acgatttggc
ctactggggc cggggaaccc tggtcaccgt ctcgtca 35798119PRTArtificial
SequenceSynthetic 98Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Thr Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Tyr Trp Val 35 40 45 Ser Ala Ile Ser Gly Gly Arg
Gly Ser Ala Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Glu
Gly Asp Ser Gly Tyr Asp Leu Ala Tyr Trp Gly Arg Gly 100 105 110Thr
Leu Val Thr Val Ser Ser 1159924DNAArtificial SequenceSynthetic
99ggattcacct ttagcagcta tgcc 241008PRTArtificial SequenceSynthetic
100Gly Phe Thr Phe Ser Ser Tyr Ala 1 510124DNAArtificial
SequenceSynthetic 101attagtggtg gtcgtggtag cgca 241028PRTArtificial
SequenceSynthetic 102Ile Ser Gly Gly Arg Gly Ser Ala 1
510336DNAArtificial SequenceSynthetic 103gcgaaagagg gggatagtgg
ctacgatttg gcctac 3610412PRTArtificial SequenceSynthetic 104Ala Lys
Glu Gly Asp Ser Gly Tyr Asp Leu Ala Tyr 1 5 10105321DNAArtificial
SequenceSynthetic 105gacatccaga tgacccagtc tccatcctca ctgtccgcat
ctgtaggaga cagagtcacc 60atcacttgtc gggcgaggca gggcattagt aataatttag
cctggcttca gcagaaacca 120gggaaagccc ctaagtccct gatctatgct
gcatccagtt tgcaaagtgg gatcccatca 180aagttcagcg gcagtggatc
tgggacatat ttcactctca ccatcagcag cctgcagcct 240gaagattttg
cgacttatta ctgccaacaa tataaaagtt ccccgctcac tttcggcgga
300gggaccaagg tggagatcaa a 321106107PRTArtificial SequenceSynthetic
106Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Arg Gln Gly Ile Ser
Asn Asn 20 25 30Leu Ala Trp Leu Gln Gln Lys Pro Gly Lys Ala Pro Lys
Ser Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Ile Pro
Ser Lys Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Tyr Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys
Gln Gln Tyr Lys Ser Ser Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys
Val Glu Ile Lys 100 10510718DNAArtificial SequenceSynthetic
107cagggcatta gtaataat 181086PRTArtificial SequenceSynthetic 108Gln
Gly Ile Ser Asn Asn 1 51099DNAArtificial SequenceSynthetic
109gctgcatcc 91103PRTArtificial SequenceSynthetic 110Ala Ala Ser
111127DNAArtificial SequenceSynthetic 111caacaatata aaagttcccc
gctcact 271129PRTArtificial SequenceSynthetic 112Gln Gln Tyr Lys
Ser Ser Pro Leu Thr 1 5113357DNAArtificial SequenceSynthetic
113gaggtgcagc tgttggagtc tgggggaggc ttggtacagc cgggggggtc
cctgagactc 60tcctgtgcag cctctggatt cacctttagc agctatgcca tgacctgggt
ccgccaggct 120ccggggaagg ggctgtattg ggtctcagct attagtggtg
gtcgtggtag cgcatactac 180gcagactccg tgaagggccg gttcaccatc
tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgcg
agccgaggac acggccgtat attactgtgc gaaagagggg 300gatagtggct
acgatttggc ctactggggc cggggaaccc tggtcaccgt ctcctca
357114119PRTArtificial SequenceSynthetic 114Glu Val Gln Leu Leu Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Thr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Tyr Trp Val 35 40 45 Ser
Ala Ile Ser Gly Gly Arg Gly Ser Ala Tyr Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95Ala Lys Glu Gly Asp Ser Gly Tyr Asp Leu Ala Tyr Trp Gly
Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser
115115321DNAArtificial SequenceSynthetic 115gacatccaga tgacccagtc
tccatcctca ctgtccgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgaggca
gggcattagt aataatttag cctggcttca gcagaaacca 120gggaaagccc
ctaagtccct gatctatgct gcatccagtt tgcaaagtgg gatcccatca
180aagttcagcg gcagtggatc tgggacatat ttcactctca ccatcagcag
cctgcagcct 240gaagattttg cgacttatta ctgccaacaa tataaaagtt
ccccgctcac tttcggcgga 300gggaccaagg tggagatcaa a
321116107PRTArtificial SequenceSynthetic 116Asp Ile Gln Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Arg Gln Gly Ile Ser Asn Asn 20 25 30Leu Ala Trp
Leu Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Ile Pro Ser Lys Phe Ser Gly 50 55
60Ser Gly Ser Gly Thr Tyr Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Lys Ser Ser Pro
Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100
105117357DNAArtificial SequenceSynthetic 117gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt
cacctttagc agctatgcca tgagctgggt ccgccaggct 120ccagggaagg
ggctggagtg ggtctcagct attagtggtg gtcgtggtag cgcatactac
180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa
cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat
attactgtgc gaaagagggg 300gatagtggct acgatttggc ctactggggc
cagggaaccc tggtcaccgt ctcctca 357118119PRTArtificial
SequenceSynthetic 118Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Gly
Arg Gly Ser Ala Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys
Glu Gly Asp Ser Gly Tyr Asp Leu Ala Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 115119322DNAArtificial
SequenceSynthetic 119gacatccaga tgacccagtc tccatcctca ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggcattagt aataatttag
cctggtttca gcagaaacca 120gggaaagccc ctaagtccct gatctatgct
gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc
tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg
caacttatta ctgccaacaa tataaaagtt ccccgctcac tttcggcgga
300gggaccaagg tggagatcaa ac 322120107PRTArtificial
SequenceSynthetic 120Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln Gly Ile Ser Asn Asn 20 25 30Leu Ala Trp Phe Gln Gln Lys Pro
Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe
Ala Thr Tyr Tyr Cys Gln Gln Tyr Lys Ser Ser Pro Leu 85 90 95Thr Phe
Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105121357DNAArtificial
SequenceSynthetic 121gaggtgcagc tgttggagtc ggggggaggc ttggtacagc
ctggggggtc cctgagactc 60tcctgtgcaa cctctggatt cacctttagc agatatacca
tgacctgggt ccgccaggct 120ccagggaagg ggctgttttg ggtctcaggt
attggtggta gtggtggtcg cgcatactac 180gcagactccg tgaagggccg
gttcaccctc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga
acagcctgag agccgaggac acggccgtat attactgtgc gaaagagggg
300gatagtggct acgatttgga ctactggggc cggggaaccc tggtcaccgt ctcgtca
357122119PRTArtificial SequenceSynthetic 122Glu Val Gln Leu Leu Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Thr Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30Thr Met Thr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Phe Trp Val 35 40 45 Ser
Gly Ile Gly Gly Ser Gly Gly Arg Ala Tyr Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Leu Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95Ala Lys Glu Gly Asp Ser Gly Tyr Asp Leu Asp Tyr Trp Gly
Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser
11512324DNAArtificial SequenceSynthetic 123ggattcacct ttagcagata
tacc 241248PRTArtificial SequenceSynthetic 124Gly Phe Thr Phe Ser
Arg Tyr Thr 1 512524DNAArtificial SequenceSynthetic 125attggtggta
gtggtggtcg cgca 241268PRTArtificial SequenceSynthetic 126Ile Gly
Gly Ser Gly Gly Arg Ala 1 512736DNAArtificial SequenceSynthetic
127gcgaaagagg gggatagtgg ctacgatttg gactac 3612812PRTArtificial
SequenceSynthetic 128Ala Lys Glu Gly Asp Ser Gly Tyr Asp Leu Asp
Tyr 1 5 10129321DNAArtificial SequenceSynthetic 129gacatccaga
tgacccagta tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc
gggcgaggca gggcataagt aattatttag cctggcttca gcagaaacca
120gggaaagccc ctaagtccct gatctatgct gcatccagtt tgcaaagggg
ggtcccatca 180aagttcagcg gcagtggatc tgggacagat ttcactctca
ccatcagcag cctgcagcct 240gaagattctg caacttatta ctgccaacaa
tataaaattt ccccgctcac tttcggcgga 300gggaccaagg tggagatcaa g
321130107PRTArtificial SequenceSynthetic 130Asp Ile Gln Met Thr Gln
Tyr Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Arg Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp
Leu Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Arg Gly Val Pro Ser Lys Phe Ser Gly 50 55
60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Tyr Lys Ile Ser Pro
Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100
10513118DNAArtificial SequenceSynthetic 131cagggcataa gtaattat
181326PRTArtificial SequenceSynthetic 132Gln Gly Ile Ser Asn Tyr 1
51339DNAArtificial SequenceSynthetic 133gctgcatcc
91343PRTArtificial SequenceSynthetic 134Ala Ala Ser
113527DNAArtificial SequenceSynthetic 135caacaatata aaatttcccc
gctcact 271369PRTArtificial SequenceSynthetic 136Gln Gln Tyr Lys
Ile Ser Pro Leu Thr 1 5137357DNAArtificial SequenceSynthetic
137gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc
cctgagactc 60tcctgtgcaa cctctggatt cacctttagc agatatacca tgacctgggt
ccgccaggct 120ccagggaagg ggctgttttg ggtctcaggt attggtggta
gtggtggtcg cgcatactac 180gcagactccg tgaagggccg gttcaccctc
tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag
agccgaggac acggccgtat attactgtgc gaaagagggg 300gatagtggct
acgatttgga ctactggggc cggggaaccc tggtcaccgt ctcctca
357138119PRTArtificial SequenceSynthetic 138Glu Val Gln Leu Leu Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Thr Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30Thr Met Thr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Phe Trp Val 35 40 45 Ser
Gly Ile Gly Gly Ser Gly Gly Arg Ala Tyr Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Leu Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95Ala Lys Glu Gly Asp Ser Gly Tyr Asp Leu Asp Tyr Trp Gly
Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser
115139321DNAArtificial SequenceSynthetic 139gacatccaga tgacccagtc
tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgaggca
gggcataagt aattatttag cctggcttca gcagaaacca 120gggaaagccc
ctaagtccct gatctatgct gcatccagtt tgcaaagggg ggtcccatca
180aagttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag
cctgcagcct 240gaagattctg caacttatta ctgccaacaa tataaaattt
ccccgctcac tttcggcgga 300gggaccaagg tggagatcaa a
321140107PRTArtificial SequenceSynthetic 140Asp Ile Gln Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Arg Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp
Leu Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Arg Gly Val Pro Ser Lys Phe Ser Gly 50 55
60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Tyr Lys Ile Ser Pro
Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100
105141357DNAArtificial SequenceSynthetic 141gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt
cacctttagc agatatacca tgagctgggt ccgccaggct 120ccagggaagg
ggctggagtg ggtctcagct attggtggta gtggtggtcg cgcatactac
180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa
cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat
attactgtgc gaaagagggg 300gatagtggct acgatttgga ctactggggc
cagggaaccc tggtcaccgt ctcctca 357142119PRTArtificial
SequenceSynthetic 142Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Arg Tyr 20 25 30Thr Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly Gly Ser
Gly Gly Arg Ala Tyr Tyr Ala Asp Ser Val
50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
Tyr Tyr Cys 85 90 95Ala Lys Glu Gly Asp Ser Gly Tyr Asp Leu Asp Tyr
Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser
115143322DNAArtificial SequenceSynthetic 143gacatccaga tgacccagtc
tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca
gggcataagt aattatttag cctggtttca gcagaaacca 120gggaaagccc
ctaagtccct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca
180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag
cctgcagcct 240gaagattttg caacttatta ctgccaacaa tataaaattt
ccccgctcac tttcggcgga 300gggaccaagg tggagatcaa ac
322144107PRTArtificial SequenceSynthetic 144Asp Ile Gln Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp
Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Lys Ile Ser Pro
Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100
105145357DNAArtificial SequenceSynthetic 145gaggtgcagc tgttggagtc
ggggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcaa cctctggatt
cacctttagc agatatacca tgacctgggt ccgccaggct 120ccagggaagg
ggctgttttg ggtctcaggt attggtggta gtggtggtcg cgcatactac
180gcagactccg tgaagggccg gttcaccctc tccagagaca attccaagaa
cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat
attactgtgc gaaagagggg 300gatagtggct acgatttgga ctactggggc
cggggaaccc tggtcaccgt ctcgtca 357146119PRTArtificial
SequenceSynthetic 146Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Thr Ser
Gly Phe Thr Phe Ser Arg Tyr 20 25 30Thr Met Thr Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Phe Trp Val 35 40 45 Ser Gly Ile Gly Gly Ser
Gly Gly Arg Ala Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Leu Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys
Glu Gly Asp Ser Gly Tyr Asp Leu Asp Tyr Trp Gly Arg Gly 100 105
110Thr Leu Val Thr Val Ser Ser 11514724DNAArtificial
SequenceSynthetic 147ggattcacct ttagcagata tacc 241488PRTArtificial
SequenceSynthetic 148Gly Phe Thr Phe Ser Arg Tyr Thr 1
514924DNAArtificial SequenceSynthetic 149attggtggta gtggtggtcg cgca
241508PRTArtificial SequenceSynthetic 150Ile Gly Gly Ser Gly Gly
Arg Ala 1 515136DNAArtificial SequenceSynthetic 151gcgaaagagg
gggatagtgg ctacgatttg gactac 3615212PRTArtificial SequenceSynthetic
152Ala Lys Glu Gly Asp Ser Gly Tyr Asp Leu Asp Tyr 1 5
10153321DNAArtificial SequenceSynthetic 153gacatccaga tgacccagta
tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgaggca
gggcataagt aattatttag cctggcttca gcagaaacca 120gggaaagccc
ctaagtccct gatctatgct gcatccagtt tgcaaagggg ggtcccatca
180aagttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag
cctgcagcct 240gaagattctg caacttatta ctgccaacaa tataaaattt
ccccgctcac tttcggcgga 300gggaccaagg tggagatcaa g
321154107PRTArtificial SequenceSynthetic 154Asp Ile Gln Met Thr Gln
Tyr Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Arg Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp
Leu Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Arg Gly Val Pro Ser Lys Phe Ser Gly 50 55
60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Tyr Lys Ile Ser Pro
Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100
10515518DNAArtificial SequenceSynthetic 155cagggcataa gtaattat
181566PRTArtificial SequenceSynthetic 156Gln Gly Ile Ser Asn Tyr 1
51579DNAArtificial SequenceSynthetic 157gctgcatcc
91583PRTArtificial SequenceSynthetic 158Ala Ala Ser
115927DNAArtificial SequenceSynthetic 159caacaatata aaatttcccc
gctcact 271609PRTArtificial SequenceSynthetic 160Gln Gln Tyr Lys
Ile Ser Pro Leu Thr 1 5161357DNAArtificial SequenceSynthetic
161gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc
cctgagactc 60tcctgtgcaa cctctggatt cacctttagc agatatacca tgacctgggt
ccgccaggct 120ccagggaagg ggctgttttg ggtctcaggt attggtggta
gtggtggtcg cgcatactac 180gcagactccg tgaagggccg gttcaccctc
tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag
agccgaggac acggccgtat attactgtgc gaaagagggg 300gatagtggct
acgatttgga ctactggggc cggggaaccc tggtcaccgt ctcctca
357162119PRTArtificial SequenceSynthetic 162Glu Val Gln Leu Leu Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Thr Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30Thr Met Thr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Phe Trp Val 35 40 45 Ser
Gly Ile Gly Gly Ser Gly Gly Arg Ala Tyr Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Leu Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95Ala Lys Glu Gly Asp Ser Gly Tyr Asp Leu Asp Tyr Trp Gly
Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser
115163321DNAArtificial SequenceSynthetic 163gacatccaga tgacccagtc
tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgaggca
gggcataagt aattatttag cctggcttca gcagaaacca 120gggaaagccc
ctaagtccct gatctatgct gcatccagtt tgcaaagggg ggtcccatca
180aagttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag
cctgcagcct 240gaagattctg caacttatta ctgccaacaa tataaaattt
ccccgctcac tttcggcgga 300gggaccaagg tggagatcaa a
321164107PRTArtificial SequenceSynthetic 164Asp Ile Gln Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Arg Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp
Leu Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Arg Gly Val Pro Ser Lys Phe Ser Gly 50 55
60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Tyr Lys Ile Ser Pro
Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100
105165357DNAArtificial SequenceSynthetic 165gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt
cacctttagc agatatacca tgagctgggt ccgccaggct 120ccagggaagg
ggctggagtg ggtctcagct attggtggta gtggtggtcg cgcatactac
180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa
cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat
attactgtgc gaaagagggg 300gatagtggct acgatttgga ctactggggc
cagggaaccc tggtcaccgt ctcctca 357166119PRTArtificial
SequenceSynthetic 166Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Arg Tyr 20 25 30Thr Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly Gly Ser
Gly Gly Arg Ala Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys
Glu Gly Asp Ser Gly Tyr Asp Leu Asp Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 115167322DNAArtificial
SequenceSynthetic 167gacatccaga tgacccagtc tccatcctca ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggcataagt aattatttag
cctggtttca gcagaaacca 120gggaaagccc ctaagtccct gatctatgct
gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc
tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg
caacttatta ctgccaacaa tataaaattt ccccgctcac tttcggcgga
300gggaccaagg tggagatcaa ac 322168107PRTArtificial
SequenceSynthetic 168Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp Phe Gln Gln Lys Pro
Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe
Ala Thr Tyr Tyr Cys Gln Gln Tyr Lys Ile Ser Pro Leu 85 90 95Thr Phe
Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105169348DNAArtificial
SequenceSynthetic 169gaagtgcagt tggtggagtc tgggggaggc ttagtacagc
ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatgcca
tgcactgggt ccggcaagct 120ccagggaagg gcctggaatg ggtctcaggt
attagttgga atagcggtag caaaggcttt 180gcggactctg tgaagggccg
gttcaccatc tccagagaca acgccaagaa ctccctctat 240ctgcaaatga
acagtctgag agttgaagac acggccttgt attactgtgc aaaagagaac
300tggtcctttg actactgggg ccagggaacc ctggtcaccg tctcctca
348170116PRTArtificial SequenceSynthetic 170Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Ser Trp Asn Ser Gly Ser Lys Gly Phe Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Leu Tyr Tyr
Cys 85 90 95Ala Lys Glu Asn Trp Ser Phe Asp Tyr Trp Gly Gln Gly Thr
Leu Val 100 105 110Thr Val Ser Ser 11517124DNAArtificial
SequenceSynthetic 171ggattcacct ttgatgatta tgcc 241728PRTArtificial
SequenceSynthetic 172Gly Phe Thr Phe Asp Asp Tyr Ala 1
517324DNAArtificial SequenceSynthetic 173attagttgga atagcggtag caaa
241748PRTArtificial SequenceSynthetic 174Ile Ser Trp Asn Ser Gly
Ser Lys 1 517527DNAArtificial SequenceSynthetic 175gcaaaagaga
actggtcctt tgactac 271769PRTArtificial SequenceSynthetic 176Ala Lys
Glu Asn Trp Ser Phe Asp Tyr 1 5177336DNAArtificial
SequenceSynthetic 177gatattgtga tgacccagac tccactctcc tcgcctgtca
cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgta cacagtgatg
gaaatatcta cttgagttgg 120cttcagcaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgaaaatc 240agcagggtgg
aagctgaaga tgtcggaatt tattattgca tgcaagcttc gcattttccg
300tacacttttg gccaggggac caagctggag atcaaa 336178112PRTArtificial
SequenceSynthetic 178Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn Ile Tyr Leu Ser Trp
Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln Ala 85 90 95Ser His
Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105
11017933DNAArtificial SequenceSynthetic 179caaagcctcg tacacagtga
tggaaatatc tac 3318011PRTArtificial SequenceSynthetic 180Gln Ser
Leu Val His Ser Asp Gly Asn Ile Tyr 1 5 101819DNAArtificial
SequenceSynthetic 181aagatttct 91823PRTArtificial SequenceSynthetic
182Lys Ile Ser 118327DNAArtificial SequenceSynthetic 183atgcaagctt
cgcattttcc gtacact 271849PRTArtificial SequenceSynthetic 184Met Gln
Ala Ser His Phe Pro Tyr Thr 1 5185348DNAArtificial
SequenceSynthetic 185gaagtgcagc tggtggagtc tgggggaggc ttagtacagc
ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatgcca
tgcactgggt ccggcaagct 120ccagggaagg gcctggaatg ggtctcaggt
attagttgga atagcggtag caaaggcttt 180gcggactctg tgaagggccg
gttcaccatc tccagagaca acgccaagaa ctccctctat 240ctgcaaatga
acagtctgag agttgaagac acggccttgt attactgtgc aaaagagaac
300tggtcctttg actactgggg ccagggaacc ctggtcaccg tctcctca
348186116PRTArtificial SequenceSynthetic 186Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Ser Trp Asn Ser Gly Ser Lys Gly Phe Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Leu Tyr Tyr
Cys 85 90 95Ala Lys Glu Asn Trp Ser Phe Asp Tyr Trp Gly Gln Gly Thr
Leu Val 100 105 110Thr Val Ser Ser 115187336DNAArtificial
SequenceSynthetic 187gatattgtga tgacccagac tccactctcc tcgcctgtca
cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgta cacagtgatg
gaaatatcta cttgagttgg 120cttcagcaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgaaaatc 240agcagggtgg
aagctgaaga tgtcggaatt tattattgca tgcaagcttc gcattttccg
300tacacttttg gccaggggac caagctggag atcaaa 336188112PRTArtificial
SequenceSynthetic 188Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn Ile Tyr Leu Ser Trp
Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln Ala 85 90 95Ser His
Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105
110189348DNAArtificial SequenceSynthetic 189gaagtgcagc tggtggagtc
tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt
cacctttgat gattatgcca tgcactgggt ccggcaagct 120ccagggaagg
gcctggagtg ggtctcaggt attagttgga atagcggtag caaaggctat
180gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa
ctccctgtat 240ctgcaaatga acagtctgag agctgaggac acggccttgt
attactgtgc aaaagagaac
300tggtcctttg actactgggg ccagggaacc ctggtcaccg tctcctca
348190116PRTArtificial SequenceSynthetic 190Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Ser Trp Asn Ser Gly Ser Lys Gly Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr
Cys 85 90 95Ala Lys Glu Asn Trp Ser Phe Asp Tyr Trp Gly Gln Gly Thr
Leu Val 100 105 110Thr Val Ser Ser 115191337DNAArtificial
SequenceSynthetic 191gatattgtga tgacccagac tccactctcc tcacctgtca
cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgta cacagtgatg
gaaatatcta cttgagttgg 120cttcagcaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgaaaatc 240agcagggtgg
aagctgagga tgtcggggtt tattactgca tgcaagcttc gcattttccg
300tacacttttg gccaggggac caagctggag atcaaac 337192112PRTArtificial
SequenceSynthetic 192Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn Ile Tyr Leu Ser Trp
Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Ser His
Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105
110193348DNAArtificial SequenceSynthetic 193gaagtgcaat tggtggagtc
tgggggaaac ttggtacagc ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt
cacctttgat gattatgcca tgcactgggt ccggcaagct 120ccagggaagg
gcctggagtg ggtctcaggt atcagttgga atagtggtag tagaggctat
180gcggactctg tgaagggccg attcaccatt tccagagaca acgccaaaaa
ctccctgtat 240ctgcaaatga acagtctgag aactgaggac acggcctttt
attattgtac aaaagaagac 300gaggcttttg actactgggg ccagggaacc
ctggtcaccg tctcctca 348194116PRTArtificial SequenceSynthetic 194Glu
Val Gln Leu Val Glu Ser Gly Gly Asn Leu Val Gln Pro Gly Arg 1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Arg Gly Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Thr Glu Asp
Thr Ala Phe Tyr Tyr Cys 85 90 95Thr Lys Glu Asp Glu Ala Phe Asp Tyr
Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser
11519524DNAArtificial SequenceSynthetic 195ggattcacct ttgatgatta
tgcc 241968PRTArtificial SequenceSynthetic 196Gly Phe Thr Phe Asp
Asp Tyr Ala 1 519724DNAArtificial SequenceSynthetic 197atcagttgga
atagtggtag taga 241988PRTArtificial SequenceSynthetic 198Ile Ser
Trp Asn Ser Gly Ser Arg 1 519927DNAArtificial SequenceSynthetic
199acaaaagaag acgaggcttt tgactac 272009PRTArtificial
SequenceSynthetic 200Thr Lys Glu Asp Glu Ala Phe Asp Tyr 1
5201336DNAArtificial SequenceSynthetic 201gatattgtga tgacccagac
tccactctcc tcacctgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca
aagcctcgta cacagtgatc gaaacaccta cttgagttgg 120cttcagcaga
ggccaggcca gcctccaaga ctccttattt ataagatttc taaccggttc
180tctggggtcc cagacagatt cagtggcagt ggggcaggga cagatttcac
actgaaaatc 240agcagggtgg aagctgagga tgtcgggttt tattactgca
tgcaggccac acaatttccg 300tacacttttg gccaggggac caaactgcag atcaat
336202112PRTArtificial SequenceSynthetic 202Asp Ile Val Met Thr Gln
Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser
Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30Asp Arg Asn
Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro
Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55
60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65
70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Phe Tyr Tyr Cys Met Gln
Ala 85 90 95Thr Gln Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Gln
Ile Asn 100 105 11020333DNAArtificial SequenceSynthetic
203caaagcctcg tacacagtga tcgaaacacc tac 3320411PRTArtificial
SequenceSynthetic 204Gln Ser Leu Val His Ser Asp Arg Asn Thr Tyr 1
5 102059DNAArtificial SequenceSynthetic 205aagatttct
92063PRTArtificial SequenceSynthetic 206Lys Ile Ser
120727DNAArtificial SequenceSynthetic 207atgcaggcca cacaatttcc
gtacact 272089PRTArtificial SequenceSynthetic 208Met Gln Ala Thr
Gln Phe Pro Tyr Thr 1 5209348DNAArtificial SequenceSynthetic
209gaagtgcagc tggtggagtc tgggggaaac ttggtacagc ctggcaggtc
cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt
ccggcaagct 120ccagggaagg gcctggagtg ggtctcaggt atcagttgga
atagtggtag tagaggctat 180gcggactctg tgaagggccg attcaccatt
tccagagaca acgccaaaaa ctccctgtat 240ctgcaaatga acagtctgag
aactgaggac acggcctttt attattgtac aaaagaagac 300gaggcttttg
actactgggg ccagggaacc ctggtcaccg tctcctca 348210116PRTArtificial
SequenceSynthetic 210Glu Val Gln Leu Val Glu Ser Gly Gly Asn Leu
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn
Ser Gly Ser Arg Gly Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Thr Glu Asp Thr Ala Phe Tyr Tyr Cys 85 90 95Thr Lys
Glu Asp Glu Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105
110Thr Val Ser Ser 115211336DNAArtificial SequenceSynthetic
211gatattgtga tgacccagac tccactctcc tcacctgtca cccttggaca
gccggcctcc 60atctcctgca ggtctagtca aagcctcgta cacagtgatc gaaacaccta
cttgagttgg 120cttcagcaga ggccaggcca gcctccaaga ctccttattt
ataagatttc taaccggttc 180tctggggtcc cagacagatt cagtggcagt
ggggcaggga cagatttcac actgaaaatc 240agcagggtgg aagctgagga
tgtcgggttt tattactgca tgcaggccac acaatttccg 300tacacttttg
gccaggggac caagctggag atcaaa 336212112PRTArtificial
SequenceSynthetic 212Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser Gln Ser Leu Val His Ser 20 25 30Asp Arg Asn Thr Tyr Leu Ser Trp
Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Phe Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln
Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105
110213348DNAArtificial SequenceSynthetic 213gaagtgcagc tggtggagtc
tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt
cacctttgat gattatgcca tgcactgggt ccggcaagct 120ccagggaagg
gcctggagtg ggtctcaggt atcagttgga atagtggtag tagaggctat
180gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa
ctccctgtat 240ctgcaaatga acagtctgag agctgaggac acggccttgt
attactgtac aaaagaagac 300gaggcttttg actactgggg ccagggaacc
ctggtcaccg tctcctca 348214116PRTArtificial SequenceSynthetic 214Glu
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Arg Gly Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Leu Tyr Tyr Cys 85 90 95Thr Lys Glu Asp Glu Ala Phe Asp Tyr
Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser
115215337DNAArtificial SequenceSynthetic 215gatattgtga tgacccagac
tccactctcc tcacctgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca
aagcctcgta cacagtgatc gaaacaccta cttgagttgg 120cttcagcaga
ggccaggcca gcctccaaga ctcctaattt ataagatttc taaccggttc
180tctggggtcc cagacagatt cagtggcagt ggggcaggga cagatttcac
actgaaaatc 240agcagggtgg aagctgagga tgtcggggtt tattactgca
tgcaggccac acaatttccg 300tacacttttg gccaggggac caagctggag atcaaac
337216112PRTArtificial SequenceSynthetic 216Asp Ile Val Met Thr Gln
Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser
Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30Asp Arg Asn
Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro
Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55
60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65
70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln
Ala 85 90 95Thr Gln Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu
Ile Lys 100 105 110217348DNAArtificial SequenceSynthetic
217gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc
cctgagactc 60tcctgtgcag cctctggctt cacctttgat gattatgcca tgcactgggt
ccggcaagct 120ccggggaagg gcctagagtg ggtctcaggt attacttgga
atagtggtac catggcctat 180gcggactctg tgaagggccg attcaccatc
tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga acagtctgag
agctgaggac acggccttat attactgtgc aaaagaaaac 300tgggcctttg
actactgggg ccagggaacc ctggtcaccg tctcctca 348218116PRTArtificial
SequenceSynthetic 218Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Thr Trp Asn
Ser Gly Thr Met Ala Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Lys
Glu Asn Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105
110Thr Val Ser Ser 11521924DNAArtificial SequenceSynthetic
219ggcttcacct ttgatgatta tgcc 242208PRTArtificial SequenceSynthetic
220Gly Phe Thr Phe Asp Asp Tyr Ala 1 522124DNAArtificial
SequenceSynthetic 221attacttgga atagtggtac catg 242228PRTArtificial
SequenceSynthetic 222Ile Thr Trp Asn Ser Gly Thr Met 1
522327DNAArtificial SequenceSynthetic 223gcaaaagaaa actgggcctt
tgactac 272249PRTArtificial SequenceSynthetic 224Ala Lys Glu Asn
Trp Ala Phe Asp Tyr 1 5225336DNAArtificial SequenceSynthetic
225gatattgtga tgacccagac tccactctcc tcacctgtca cccttggaca
gccggcctcc 60atctcctgca ggtctagtca cagcctcgta cacagtgatg gaaacaccta
cttgagttgg 120cttcagcaga ggccaggcca gcctccaaga ctcctaattt
ataagatttc taaccggttc 180tctggggtcc cagacagatt cagtggcagt
ggggcaggga cagatttcac actgaaaatc 240agcagggtgg aagctgagga
tgtcggggtt tatttctgca tgcaagctac acaatttccg 300tacacttttg
gccaggggac caagctggag atcaaa 336226112PRTArtificial
SequenceSynthetic 226Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser His Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp
Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Met Gln Ala 85 90 95Thr Gln
Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105
11022733DNAArtificial SequenceSynthetic 227cacagcctcg tacacagtga
tggaaacacc tac 3322811PRTArtificial SequenceSynthetic 228His Ser
Leu Val His Ser Asp Gly Asn Thr Tyr 1 5 102299DNAArtificial
SequenceSynthetic 229aagatttct 92303PRTArtificial SequenceSynthetic
230Lys Ile Ser 123127DNAArtificial SequenceSynthetic 231atgcaagcta
cacaatttcc gtacact 272329PRTArtificial SequenceSynthetic 232Met Gln
Ala Thr Gln Phe Pro Tyr Thr 1 5233348DNAArtificial
SequenceSynthetic 233gaagtgcagc tggtggagtc tgggggaggc ttggtacagc
ctggcaggtc cctgagactc 60tcctgtgcag cctctggctt cacctttgat gattatgcca
tgcactgggt ccggcaagct 120ccggggaagg gcctagagtg ggtctcaggt
attacttgga atagtggtac catggcctat 180gcggactctg tgaagggccg
attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga
acagtctgag agctgaggac acggccttat attactgtgc aaaagaaaac
300tgggcctttg actactgggg ccagggaacc ctggtcaccg tctcctca
348234116PRTArtificial SequenceSynthetic 234Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Thr Trp Asn Ser Gly Thr Met Ala Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr
Cys 85 90 95Ala Lys Glu Asn Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr
Leu Val 100 105 110Thr Val Ser Ser 115235336DNAArtificial
SequenceSynthetic 235gatattgtga tgacccagac tccactctcc tcacctgtca
cccttggaca gccggcctcc 60atctcctgca ggtctagtca cagcctcgta cacagtgatg
gaaacaccta cttgagttgg 120cttcagcaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgaaaatc 240agcagggtgg
aagctgagga tgtcggggtt tatttctgca tgcaagctac acaatttccg
300tacacttttg gccaggggac caagctggag atcaaa 336236112PRTArtificial
SequenceSynthetic 236Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser His Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp
Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr
Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr
Phe Cys Met Gln Ala 85 90 95Thr Gln Phe Pro Tyr Thr Phe Gly Gln Gly
Thr Lys Leu Glu Ile Lys 100 105 110237348DNAArtificial
SequenceSynthetic 237gaagtgcagc tggtggagtc tgggggaggc ttggtacagc
ctggcaggtc cctgagactc 60tcctgtgcag cctctggctt cacctttgat gattatgcca
tgcactgggt ccggcaagct 120ccagggaagg gcctggagtg ggtctcaggt
attacttgga atagtggtac catgggctat 180gcggactctg tgaagggccg
attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga
acagtctgag agctgaggac acggccttgt attactgtgc aaaagaaaac
300tgggcctttg actactgggg ccagggaacc ctggtcaccg tctcctca
348238116PRTArtificial SequenceSynthetic 238Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Thr Trp Asn Ser Gly Thr Met Gly Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr
Cys 85 90 95Ala Lys Glu Asn Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr
Leu Val 100 105 110Thr Val Ser Ser 115239337DNAArtificial
SequenceSynthetic 239gatattgtga tgacccagac tccactctcc tcacctgtca
cccttggaca gccggcctcc 60atctcctgca ggtctagtca cagcctcgta cacagtgatg
gaaacaccta cttgagttgg 120cttcagcaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgaaaatc 240agcagggtgg
aagctgagga tgtcggggtt tattactgca tgcaagctac acaatttccg
300tacacttttg gccaggggac caagctggag atcaaac 337240112PRTArtificial
SequenceSynthetic 240Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser His Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp
Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln
Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105
110241384DNAArtificial SequenceSynthetic 241gaagtgcagc tggtggagtc
tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt
cacctttgat gattatgcca tgcactgggt ccggcaagct 120ccagggaagg
gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat
180gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa
ctccctgtat 240ctgcaaatga acagtctgag agctgaggac acggccttgt
attactgtgc aaaagataga 300ttccctccgt ataagtataa cagtggtggt
ttttctgatg cttttgaaat ctggggccaa 360gggacaatgg tcaccgtctc ttca
384242128PRTArtificial SequenceSynthetic 242Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr
Cys 85 90 95Ala Lys Asp Arg Phe Pro Pro Tyr Lys Tyr Asn Ser Gly Gly
Phe Ser 100 105 110Asp Ala Phe Glu Ile Trp Gly Gln Gly Thr Met Val
Thr Val Ser Ser 115 120 12524324DNAArtificial SequenceSynthetic
243ggattcacct ttgatgatta tgcc 242448PRTArtificial SequenceSynthetic
244Gly Phe Thr Phe Asp Asp Tyr Ala 1 524524DNAArtificial
SequenceSynthetic 245attagttgga atagtggtag cata 242468PRTArtificial
SequenceSynthetic 246Ile Ser Trp Asn Ser Gly Ser Ile 1
524763DNAArtificial SequenceSynthetic 247gcaaaagata gattccctcc
gtataagtat aacagtggtg gtttttctga tgcttttgaa 60atc
6324821PRTArtificial SequenceSynthetic 248Ala Lys Asp Arg Phe Pro
Pro Tyr Lys Tyr Asn Ser Gly Gly Phe Ser 1 5 10 15Asp Ala Phe Glu
Ile 20249324DNAArtificial SequenceSynthetic 249gaaattgtgt
tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca
gggccagtca gagttttagc agcagctact tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac
tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc
tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag
cagtatggta gttcaccgat caccttcggc 300caagggacac gactggagat tgaa
324250108PRTArtificial SequenceSynthetic 250Glu Ile Val Leu Thr Gln
Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15Glu Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln Ser Phe Ser Ser Ser 20 25 30Tyr Leu Ala
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55
60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65
70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser
Pro 85 90 95Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Glu 100
10525121DNAArtificial SequenceSynthetic 251cagagtttta gcagcagcta c
212527PRTArtificial SequenceSynthetic 252Gln Ser Phe Ser Ser Ser
Tyr 1 52539DNAArtificial SequenceSynthetic 253ggtgcatcc
92543PRTArtificial SequenceSynthetic 254Gly Ala Ser
125527DNAArtificial SequenceSynthetic 255cagcagtatg gtagttcacc
gatcacc 272569PRTArtificial SequenceSynthetic 256Gln Gln Tyr Gly
Ser Ser Pro Ile Thr 1 5257384DNAArtificial SequenceSynthetic
257gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc
cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt
ccggcaagct 120ccagggaagg gcctggagtg ggtctcaggt attagttgga
atagtggtag cataggctat 180gcggactctg tgaagggccg attcaccatc
tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga acagtctgag
agctgaggac acggccttgt attactgtgc aaaagataga 300ttccctccgt
ataagtataa cagtggtggt ttttctgatg cttttgaaat ctggggccaa
360gggacaatgg tcaccgtctc ttca 384258128PRTArtificial
SequenceSynthetic 258Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn
Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Lys
Asp Arg Phe Pro Pro Tyr Lys Tyr Asn Ser Gly Gly Phe Ser 100 105
110Asp Ala Phe Glu Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120 125259324DNAArtificial SequenceSynthetic 259gaaattgtgt
tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca
gggccagtca gagttttagc agcagctact tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac
tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc
tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag
cagtatggta gttcaccgat caccttcggc 300caagggacac gactggagat taaa
324260108PRTArtificial SequenceSynthetic 260Glu Ile Val Leu Thr Gln
Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15Glu Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln Ser Phe Ser Ser Ser 20 25 30Tyr Leu Ala
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55
60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65
70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser
Pro 85 90 95Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100
105261384DNAArtificial SequenceSynthetic 261gaagtgcagc tggtggagtc
tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt
cacctttgat gattatgcca tgcactgggt ccggcaagct 120ccagggaagg
gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat
180gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa
ctccctgtat 240ctgcaaatga acagtctgag agctgaggac acggccttgt
attactgtgc aaaagataga 300ttccctccgt ataagtataa cagtggtggt
ttttctgatg cttttgaaat ctggggccaa 360gggacaatgg tcaccgtctc ttca
384262128PRTArtificial SequenceSynthetic 262Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr
Cys 85 90 95Ala Lys Asp Arg Phe Pro Pro Tyr Lys Tyr Asn Ser Gly Gly
Phe Ser 100 105 110Asp Ala Phe Glu Ile Trp Gly Gln Gly Thr Met Val
Thr Val Ser Ser 115 120 125263325DNAArtificial SequenceSynthetic
263gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga
aagagccacc 60ctctcctgca gggccagtca gagttttagc agcagctact tagcctggta
ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca
gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca
gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta
ttactgtcag cagtatggta gttcaccgat caccttcggc 300caagggacac
gactggagat taaac 325264108PRTArtificial SequenceSynthetic 264Glu
Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Phe Ser Ser Ser
20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu
Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp
Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln
Gln Tyr Gly Ser Ser Pro 85 90 95Ile Thr Phe Gly Gln Gly Thr Arg Leu
Glu Ile Lys 100 105265366DNAArtificial SequenceSynthetic
265gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc
cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctacgaca tgcactgggt
ccgccaagtt 120acaggaaaag gtctggaatg ggtctcagtc attggtactg
ttggtgacac atactatcca 180ggctccctga agggccgatt caccatctcc
agagaaaatg ccaagaactc cttgtatctt 240caaatgaaca ccctgagagc
cggggacacg gctgtttatt actgtgcaag aactggagca 300gcagcccact
cgtactacta cggtatggac gtctggggcc aagggaccat ggtcaccgtc 360tcctca
366266122PRTArtificial SequenceSynthetic 266Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Asp Met His
Trp Val Arg Gln Val Thr Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Val Ile Gly Thr Val Gly Asp Thr Tyr Tyr Pro Gly Ser Leu Lys 50 55
60Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Ser Leu Tyr Leu65
70 75 80Gln Met Asn Thr Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr Cys
Ala 85 90 95Arg Thr Gly Ala Ala Ala His Ser Tyr Tyr Tyr Gly Met Asp
Val Trp 100 105 110Gly Gln Gly Thr Met Val Thr Val Ser Ser 115
12026724DNAArtificial SequenceSynthetic 267ggattcacct tcagtagcta
cgac 242688PRTArtificial SequenceSynthetic 268Gly Phe Thr Phe Ser
Ser Tyr Asp 1 526921DNAArtificial SequenceSynthetic 269attggtactg
ttggtgacac a 212707PRTArtificial SequenceSynthetic 270Ile Gly Thr
Val Gly Asp Thr 1 527148DNAArtificial SequenceSynthetic
271gcaagaactg gagcagcagc ccactcgtac tactacggta tggacgtc
4827216PRTArtificial SequenceSynthetic 272Ala Arg Thr Gly Ala Ala
Ala His Ser Tyr Tyr Tyr Gly Met Asp Val 1 5 10
15273336DNAArtificial SequenceSynthetic 273gatattgtga tgactcagtc
tccactctcc ctgcccgtca cccctggaga gccggcctcc 60atctcctgca ggtctagtca
gagcctcctg tatagtaatg gatacaacta tttggattgg 120tacctacaga
agccagggca gtctccacag ctcctgatct atttgggttc taatcgggcc
180tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac
actgaaaatc 240agcagagtgg aggctgagga tgttggaatt tattactgca
tgcaagctct acaaactccg 300tggacgttcg gccaagggac caaggtggaa atcaaa
336274112PRTArtificial SequenceSynthetic 274Asp Ile Val Met Thr Gln
Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15Glu Pro Ala Ser
Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30Asn Gly Tyr
Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro
Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55
60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65
70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln
Ala 85 90 95Leu Gln Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu
Ile Lys 100 105 11027533DNAArtificial SequenceSynthetic
275cagagcctcc tgtatagtaa tggatacaac tat 3327611PRTArtificial
SequenceSynthetic 276Gln Ser Leu Leu Tyr Ser Asn Gly Tyr Asn Tyr 1
5 102779DNAArtificial SequenceSynthetic 277ttgggttct
92783PRTArtificial SequenceSynthetic 278Leu Gly Ser
127927DNAArtificial SequenceSynthetic 279atgcaagctc tacaaactcc
gtggacg 272809PRTArtificial SequenceSynthetic 280Met Gln Ala Leu
Gln Thr Pro Trp Thr 1 5281363DNAArtificial SequenceSynthetic
281gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc
cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctacgaca tgcactgggt
ccgccaagtt 120acaggaaaag gtctggaatg ggtctcagtc attggtactg
ttggtgacac atactatcca 180ggctccctga agggccgatt caccatctcc
agagaaaatg ccaagaactc cttgtatctt 240caaatgaaca ccctgagagc
cggggacacg gctgtttatt actgtgcaag aactggagca 300gcagcccact
cgtactacta cggtatggac gtctggggcc aagggaccac ggtcaccgtc 360tcc
363282121PRTArtificial SequenceSynthetic 282Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Asp Met His
Trp Val Arg Gln Val Thr Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Val Ile Gly Thr Val Gly Asp Thr Tyr Tyr Pro Gly Ser Leu Lys 50 55
60Gly
Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Ser Leu Tyr Leu65 70 75
80Gln Met Asn Thr Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95Arg Thr Gly Ala Ala Ala His Ser Tyr Tyr Tyr Gly Met Asp Val
Trp 100 105 110Gly Gln Gly Thr Thr Val Thr Val Ser 115
120283336DNAArtificial SequenceSynthetic 283gatattgtga tgactcagtc
tccactctcc ctgcccgtca cccctggaga gccggcctcc 60atctcctgca ggtctagtca
gagcctcctg tatagtaatg gatacaacta tttggattgg 120tacctacaga
agccagggca gtctccacag ctcctgatct atttgggttc taatcgggcc
180tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac
actgaaaatc 240agcagagtgg aggctgagga tgttggaatt tattactgca
tgcaagctct acaaactccg 300tggacgttcg gccaagggac caaggtggaa atcaaa
336284112PRTArtificial SequenceSynthetic 284Asp Ile Val Met Thr Gln
Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15Glu Pro Ala Ser
Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30Asn Gly Tyr
Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro
Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55
60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65
70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln
Ala 85 90 95Leu Gln Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu
Ile Lys 100 105 110285364DNAArtificial SequenceSynthetic
285gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc
cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctacgaca tgcactgggt
ccgccaagct 120acaggaaaag gtctggagtg ggtctcagct attggtactg
ttggtgacac atactatcca 180ggctccgtga agggccgatt caccatctcc
agagaaaatg ccaagaactc cttgtatctt 240caaatgaaca gcctgagagc
cggggacacg gctgtgtatt actgtgcaag aactggagca 300gcagcccact
cgtactacta cggtatggac gtctggggcc aagggaccac ggtcaccgtc 360tcct
364286121PRTArtificial SequenceSynthetic 286Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Asp Met His
Trp Val Arg Gln Ala Thr Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ala Ile Gly Thr Val Gly Asp Thr Tyr Tyr Pro Gly Ser Val Lys 50 55
60Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Ser Leu Tyr Leu65
70 75 80Gln Met Asn Ser Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr Cys
Ala 85 90 95Arg Thr Gly Ala Ala Ala His Ser Tyr Tyr Tyr Gly Met Asp
Val Trp 100 105 110Gly Gln Gly Thr Thr Val Thr Val Ser 115
120287337DNAArtificial SequenceSynthetic 287gatattgtga tgactcagtc
tccactctcc ctgcccgtca cccctggaga gccggcctcc 60atctcctgca ggtctagtca
gagcctcctg tatagtaatg gatacaacta tttggattgg 120tacctgcaga
agccagggca gtctccacag ctcctgatct atttgggttc taatcgggcc
180tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac
actgaaaatc 240agcagagtgg aggctgagga tgttggggtt tattactgca
tgcaagctct acaaactccg 300tggacgttcg gccaagggac caaggtggaa atcaaac
337288112PRTArtificial SequenceSynthetic 288Asp Ile Val Met Thr Gln
Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15Glu Pro Ala Ser
Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30Asn Gly Tyr
Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro
Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55
60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65
70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln
Ala 85 90 95Leu Gln Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu
Ile Lys 100 105 110289357DNAArtificial SequenceSynthetic
289gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc
cctgagactc 60tcctgtgcag cctctggatt cacctttagc agctatgcca tgacctgggt
ccgccaggct 120ccagggaagg ggctgtattg ggtctcagct attagtggta
gtggtggtag cgcatactac 180gcagactccg tgaagggccg gttcaccatc
tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag
agccgaggac acggccgtat attactgtgc gaaagagggg 300gatagtggct
acgatttgga ctactggggc cggggaaccc tggtcaccgt ctcgtca
357290119PRTArtificial SequenceSynthetic 290Glu Val Gln Leu Leu Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Thr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Tyr Trp Val 35 40 45 Ser
Ala Ile Ser Gly Ser Gly Gly Ser Ala Tyr Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95Ala Lys Glu Gly Asp Ser Gly Tyr Asp Leu Asp Tyr Trp Gly
Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser
11529124DNAArtificial SequenceSynthetic 291ggattcacct ttagcagcta
tgcc 242928PRTArtificial SequenceSynthetic 292Gly Phe Thr Phe Ser
Ser Tyr Ala 1 529324DNAArtificial SequenceSynthetic 293attagtggta
gtggtggtag cgca 242948PRTArtificial SequenceSynthetic 294Ile Ser
Gly Ser Gly Gly Ser Ala 1 529536DNAArtificial SequenceSynthetic
295gcgaaagagg gggatagtgg ctacgatttg gactac 3629612PRTArtificial
SequenceSynthetic 296Ala Lys Glu Gly Asp Ser Gly Tyr Asp Leu Asp
Tyr 1 5 10297321DNAArtificial SequenceSynthetic 297gacatccaga
tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc
gggcgaggca gggcattagt aattatttag cctggcttca gcagaaacca
120gggaaagccc ctaagtccct gatctatgct gcatccagtt tgcaaagtgg
ggtcccatca 180aagttcagcg gcagtggatc tgggacagat ttcactctca
ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgccaacaa
tataaaagtt ccccgctcac tttcggcgga 300gggaccaagg tggagatcaa a
321298107PRTArtificial SequenceSynthetic 298Asp Ile Gln Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Arg Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp
Leu Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55
60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Lys Ser Ser Pro
Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100
10529918DNAArtificial SequenceSynthetic 299cagggcatta gtaattat
183006PRTArtificial SequenceSynthetic 300Gln Gly Ile Ser Asn Tyr 1
53019DNAArtificial SequenceSynthetic 301gctgcatcc
93023PRTArtificial SequenceSynthetic 302Ala Ala Ser
130327DNAArtificial SequenceSynthetic 303caacaatata aaagttcccc
gctcact 273049PRTArtificial SequenceSynthetic 304Gln Gln Tyr Lys
Ser Ser Pro Leu Thr 1 5305357DNAArtificial SequenceSynthetic
305gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc
cctgagactc 60tcctgtgcag cctctggatt cacctttagc agctatgcca tgacctgggt
ccgccaggct 120ccagggaagg ggctgtattg ggtctcagct attagtggta
gtggtggtag cgcatactac 180gcagactccg tgaagggccg gttcaccatc
tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag
agccgaggac acggccgtat attactgtgc gaaagagggg 300gatagtggct
acgatttgga ctactggggc cggggaaccc tggtcaccgt ctcctca
357306119PRTArtificial SequenceSynthetic 306Glu Val Gln Leu Leu Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Thr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Tyr Trp Val 35 40 45 Ser
Ala Ile Ser Gly Ser Gly Gly Ser Ala Tyr Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95Ala Lys Glu Gly Asp Ser Gly Tyr Asp Leu Asp Tyr Trp Gly
Arg Gly 100 105 110Thr Leu Val Thr Val Ser Ser
115307321DNAArtificial SequenceSynthetic 307gacatccaga tgacccagtc
tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgaggca
gggcattagt aattatttag cctggcttca gcagaaacca 120gggaaagccc
ctaagtccct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca
180aagttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag
cctgcagcct 240gaagattttg caacttatta ctgccaacaa tataaaagtt
ccccgctcac tttcggcgga 300gggaccaagg tggagatcaa a
321308107PRTArtificial SequenceSynthetic 308Asp Ile Gln Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Arg Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp
Leu Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55
60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Lys Ser Ser Pro
Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100
105309357DNAArtificial SequenceSynthetic 309gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt
cacctttagc agctatgcca tgagctgggt ccgccaggct 120ccagggaagg
ggctggagtg ggtctcagct attagtggta gtggtggtag cgcatactac
180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa
cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat
attactgtgc gaaagagggg 300gatagtggct acgatttgga ctactggggc
cagggaaccc tggtcaccgt ctcctca 357310119PRTArtificial
SequenceSynthetic 310Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser
Gly Gly Ser Ala Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys
Glu Gly Asp Ser Gly Tyr Asp Leu Asp Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 115311322DNAArtificial
SequenceSynthetic 311gacatccaga tgacccagtc tccatcctca ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggcattagt aattatttag
cctggtttca gcagaaacca 120gggaaagccc ctaagtccct gatctatgct
gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc
tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg
caacttatta ctgccaacaa tataaaagtt ccccgctcac tttcggcgga
300gggaccaagg tggagatcaa ac 322312107PRTArtificial
SequenceSynthetic 312Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp Phe Gln Gln Lys Pro
Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe
Ala Thr Tyr Tyr Cys Gln Gln Tyr Lys Ser Ser Pro Leu 85 90 95Thr Phe
Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105313348DNAArtificial
SequenceSynthetic 313gaagtgcagt tggtggagtc tgggggaggc ttggtacagc
ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatgcca
tgcactgggt ccggcaagtt 120ccagggaagg gcctggagtg ggtctcaggt
attacttgga atagtggtag catagactat 180gcggactctg tgaagggccg
attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga
acagtctgag agctgaggac acggccttct attattgtgt aaaagaagat
300gaggcttttg actactgggg ccagggaacc ctggtcaccg tctcctca
348314116PRTArtificial SequenceSynthetic 314Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His
Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Thr Trp Asn Ser Gly Ser Ile Asp Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Phe Tyr Tyr
Cys 85 90 95Val Lys Glu Asp Glu Ala Phe Asp Tyr Trp Gly Gln Gly Thr
Leu Val 100 105 110Thr Val Ser Ser 11531524DNAArtificial
SequenceSynthetic 315ggattcacct ttgatgatta tgcc 243168PRTArtificial
SequenceSynthetic 316Gly Phe Thr Phe Asp Asp Tyr Ala 1
531724DNAArtificial SequenceSynthetic 317attacttgga atagtggtag cata
243188PRTArtificial SequenceSynthetic 318Ile Thr Trp Asn Ser Gly
Ser Ile 1 531927DNAArtificial SequenceSynthetic 319gtaaaagaag
atgaggcttt tgactac 273209PRTArtificial SequenceSynthetic 320Val Lys
Glu Asp Glu Ala Phe Asp Tyr 1 5321336DNAArtificial
SequenceSynthetic 321gatattgtga tgacccagac tccactctcc tcacctgtca
cccttggaca gccggcctcc 60atctcctgta ggtctagtca aagcctcgta cacagtgatg
gaaacaccta tttgagttgg 120cttcagcaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagaat
cagtggcagt ggggcaggga cagatttcac actgaaaatc 240agcagggtgg
aggctgagga tgtcggcgtt tattattgca tgcaagctac acaatttccg
300tacacttttg gccaggggac caagctggag atcaaa 336322112PRTArtificial
SequenceSynthetic 322Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp
Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Ile Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln
Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105
11032333DNAArtificial SequenceSynthetic 323caaagcctcg tacacagtga
tggaaacacc tat 3332411PRTArtificial SequenceSynthetic 324Gln Ser
Leu Val His Ser Asp Gly Asn Thr Tyr 1 5 103259DNAArtificial
SequenceSynthetic 325aagatttct 93263PRTArtificial SequenceSynthetic
326Lys Ile Ser 132727DNAArtificial SequenceSynthetic 327atgcaagcta
cacaatttcc gtacact 273289PRTArtificial SequenceSynthetic 328Met Gln
Ala Thr Gln Phe Pro Tyr Thr 1 5329348DNAArtificial
SequenceSynthetic 329gaagtgcagc tggtggagtc tgggggaggc ttggtacagc
ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatgcca
tgcactgggt ccggcaagtt 120ccagggaagg gcctggagtg ggtctcaggt
attacttgga
atagtggtag catagactat 180gcggactctg tgaagggccg attcaccatc
tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga acagtctgag
agctgaggac acggccttct attattgtgt aaaagaagat 300gaggcttttg
actactgggg ccagggaacc ctggtcaccg tctcctca 348330116PRTArtificial
SequenceSynthetic 330Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His Trp Val Arg Gln Val
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Thr Trp Asn
Ser Gly Ser Ile Asp Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Phe Tyr Tyr Cys 85 90 95Val Lys
Glu Asp Glu Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105
110Thr Val Ser Ser 115331336DNAArtificial SequenceSynthetic
331gatattgtga tgacccagac tccactctcc tcacctgtca cccttggaca
gccggcctcc 60atctcctgta ggtctagtca aagcctcgta cacagtgatg gaaacaccta
tttgagttgg 120cttcagcaga ggccaggcca gcctccaaga ctcctaattt
ataagatttc taaccggttc 180tctggggtcc cagacagaat cagtggcagt
ggggcaggga cagatttcac actgaaaatc 240agcagggtgg aggctgagga
tgtcggcgtt tattattgca tgcaagctac acaatttccg 300tacacttttg
gccaggggac caagctggag atcaaa 336332112PRTArtificial
SequenceSynthetic 332Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp
Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Ile Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln
Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105
110333348DNAArtificial SequenceSynthetic 333gaagtgcagc tggtggagtc
tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt
cacctttgat gattatgcca tgcactgggt ccggcaagct 120ccagggaagg
gcctggagtg ggtctcaggt attacttgga atagtggtag cataggctat
180gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa
ctccctgtat 240ctgcaaatga acagtctgag agctgaggac acggccttgt
attactgtgt aaaagaagat 300gaggcttttg actactgggg ccagggaacc
ctggtcaccg tctcctca 348334116PRTArtificial SequenceSynthetic 334Glu
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45 Ser Gly Ile Thr Trp Asn Ser Gly Ser Ile Gly Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Leu Tyr Tyr Cys 85 90 95Val Lys Glu Asp Glu Ala Phe Asp Tyr
Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser
115335337DNAArtificial SequenceSynthetic 335gatattgtga tgacccagac
tccactctcc tcacctgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca
aagcctcgta cacagtgatg gaaacaccta tttgagttgg 120cttcagcaga
ggccaggcca gcctccaaga ctcctaattt ataagatttc taaccggttc
180tctggggtcc cagacagatt cagtggcagt ggggcaggga cagatttcac
actgaaaatc 240agcagggtgg aagctgagga tgtcggggtt tattactgca
tgcaagctac acaatttccg 300tacacttttg gccaggggac caagctggag atcaaac
337336112PRTArtificial SequenceSynthetic 336Asp Ile Val Met Thr Gln
Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser
Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn
Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro
Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55
60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65
70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln
Ala 85 90 95Thr Gln Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu
Ile Lys 100 105 110337357DNAArtificial SequenceSynthetic
337gaggtgcaac tgttggagtc tgggggaggc ttggtacagc ctggggggtc
cctgagactc 60tcctgtgcag cctctggatt cacctttaga agttatacca tgacctgggt
ccgccaggct 120ccagggaagg gactggattg ggtctcaggt attactgata
gtggtgctgg cacatactac 180ggagactccg tgaagggccg gttcaccatc
tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag
agccgaggac acggccgtgt attactgtgt gaaagagggg 300gatagtggct
acgatttgga ctactggggc cagggaaccc tggtcaccgt ctcctca
357338119PRTArtificial SequenceSynthetic 338Glu Val Gln Leu Leu Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Tyr 20 25 30Thr Met Thr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp Val 35 40 45 Ser
Gly Ile Thr Asp Ser Gly Ala Gly Thr Tyr Tyr Gly Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95Val Lys Glu Gly Asp Ser Gly Tyr Asp Leu Asp Tyr Trp Gly
Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser
11533924DNAArtificial SequenceSynthetic 339ggattcacct ttagaagtta
tacc 243408PRTArtificial SequenceSynthetic 340Gly Phe Thr Phe Arg
Ser Tyr Thr 1 534124DNAArtificial SequenceSynthetic 341attactgata
gtggtgctgg caca 243428PRTArtificial SequenceSynthetic 342Ile Thr
Asp Ser Gly Ala Gly Thr 1 534336DNAArtificial SequenceSynthetic
343gtgaaagagg gggatagtgg ctacgatttg gactac 3634412PRTArtificial
SequenceSynthetic 344Val Lys Glu Gly Asp Ser Gly Tyr Asp Leu Asp
Tyr 1 5 10345321DNAArtificial SequenceSynthetic 345gacatccaga
tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc
gggcgagtca gggcattagt acttatttag cctggcttca gcagaaacca
120gggaaagccc ctaagtccct gatctatgct acatccagtt tgcaaagtgg
ggtcccatca 180aagttcagcg gcagtagatc tgggacagat ttcactctca
ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgccaacaa
tataagagtt ccccgctcac tttcggcgga 300gggaccaagg tggagatcaa a
321346107PRTArtificial SequenceSynthetic 346Asp Ile Gln Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Thr Tyr 20 25 30Leu Ala Trp
Leu Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr
Ala Thr Ser Ser Leu Gln Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55
60Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Lys Ser Ser Pro
Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100
10534718DNAArtificial SequenceSynthetic 347cagggcatta gtacttat
183486PRTArtificial SequenceSynthetic 348Gln Gly Ile Ser Thr Tyr 1
53499DNAArtificial SequenceSynthetic 349gctacatcc
93503PRTArtificial SequenceSynthetic 350Ala Thr Ser
135127DNAArtificial SequenceSynthetic 351caacaatata agagttcccc
gctcact 273529PRTArtificial SequenceSynthetic 352Gln Gln Tyr Lys
Ser Ser Pro Leu Thr 1 5353357DNAArtificial SequenceSynthetic
353gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc
cctgagactc 60tcctgtgcag cctctggatt cacctttaga agttatacca tgacctgggt
ccgccaggct 120ccagggaagg gactggattg ggtctcaggt attactgata
gtggtgctgg cacatactac 180ggagactccg tgaagggccg gttcaccatc
tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag
agccgaggac acggccgtgt attactgtgt gaaagagggg 300gatagtggct
acgatttgga ctactggggc cagggaaccc tggtcaccgt ctcctca
357354119PRTArtificial SequenceSynthetic 354Glu Val Gln Leu Leu Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Tyr 20 25 30Thr Met Thr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp Val 35 40 45 Ser
Gly Ile Thr Asp Ser Gly Ala Gly Thr Tyr Tyr Gly Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95Val Lys Glu Gly Asp Ser Gly Tyr Asp Leu Asp Tyr Trp Gly
Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser
115355321DNAArtificial SequenceSynthetic 355gacatccaga tgacccagtc
tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca
gggcattagt acttatttag cctggcttca gcagaaacca 120gggaaagccc
ctaagtccct gatctatgct acatccagtt tgcaaagtgg ggtcccatca
180aagttcagcg gcagtagatc tgggacagat ttcactctca ccatcagcag
cctgcagcct 240gaagattttg caacttatta ctgccaacaa tataagagtt
ccccgctcac tttcggcgga 300gggaccaagg tggagatcaa a
321356107PRTArtificial SequenceSynthetic 356Asp Ile Gln Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Thr Tyr 20 25 30Leu Ala Trp
Leu Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr
Ala Thr Ser Ser Leu Gln Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55
60Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Lys Ser Ser Pro
Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100
105357357DNAArtificial SequenceSynthetic 357gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt
cacctttaga agttatacca tgagctgggt ccgccaggct 120ccagggaagg
ggctggagtg ggtctcagct attactgata gtggtgctgg cacatactac
180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa
cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat
attactgtgt gaaagagggg 300gatagtggct acgatttgga ctactggggc
cagggaaccc tggtcaccgt ctcctca 357358119PRTArtificial
SequenceSynthetic 358Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Arg Ser Tyr 20 25 30Thr Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Asp Ser
Gly Ala Gly Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Val Lys
Glu Gly Asp Ser Gly Tyr Asp Leu Asp Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 115359322DNAArtificial
SequenceSynthetic 359gacatccaga tgacccagtc tccatcctca ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggcattagt acttatttag
cctggtttca gcagaaacca 120gggaaagccc ctaagtccct gatctatgct
acatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc
tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg
caacttatta ctgccaacaa tataagagtt ccccgctcac tttcggcgga
300gggaccaagg tggagatcaa ac 322360107PRTArtificial
SequenceSynthetic 360Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln Gly Ile Ser Thr Tyr 20 25 30Leu Ala Trp Phe Gln Gln Lys Pro
Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr Ala Thr Ser Ser Leu
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe
Ala Thr Tyr Tyr Cys Gln Gln Tyr Lys Ser Ser Pro Leu 85 90 95Thr Phe
Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105361348DNAArtificial
SequenceSynthetic 361gaagtgcaac tggtggagtc tgggggagac ttggtacagc
ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatgcca
tgcactgggt ccggcaagct 120ccagggaggg gcctagagtg ggtctcaggt
attacttgga atagtggtac catggcctat 180gcggactctg tggagggccg
attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctacaaatga
acagtctgag agctgaggac acggccttat attactgtgc aagagaaaac
300tgggcctttg actactgggg ccagggaacc ctggtcaccg tctcctca
348362116PRTArtificial SequenceSynthetic 362Glu Val Gln Leu Val Glu
Ser Gly Gly Asp Leu Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His
Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Thr Trp Asn Ser Gly Thr Met Ala Tyr Ala Asp Ser Val 50 55
60Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr
Cys 85 90 95Ala Arg Glu Asn Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr
Leu Val 100 105 110Thr Val Ser Ser 11536324DNAArtificial
SequenceSynthetic 363ggattcacct ttgatgatta tgcc 243648PRTArtificial
SequenceSynthetic 364Gly Phe Thr Phe Asp Asp Tyr Ala 1
536524DNAArtificial SequenceSynthetic 365attacttgga atagtggtac catg
243668PRTArtificial SequenceSynthetic 366Ile Thr Trp Asn Ser Gly
Thr Met 1 536727DNAArtificial SequenceSynthetic 367gcaagagaaa
actgggcctt tgactac 273689PRTArtificial SequenceSynthetic 368Ala Arg
Glu Asn Trp Ala Phe Asp Tyr 1 5369336DNAArtificial
SequenceSynthetic 369gatattgtga tgacccagac tccactctcc tcacctgtca
cccttggaca gccggcctcc 60atctcctgca ggtctagtca cagcctcgta cacagtgatg
gaaacaccta cttgagttgg 120cttcagcaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt gggccaggga cagatttcac actgaaaatc 240agcagggtgg
aagctgagga tgtcggggtt tatttctgca tgcaagctac acaatttccg
300tacacttttg gccaggggac caagctggag atcaaa 336370112PRTArtificial
SequenceSynthetic 370Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser His Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp
Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Pro Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Met Gln Ala 85 90 95Thr Gln
Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105
11037133DNAArtificial SequenceSynthetic 371cacagcctcg tacacagtga
tggaaacacc tac 3337211PRTArtificial SequenceSynthetic 372His Ser
Leu Val His Ser Asp Gly Asn Thr Tyr 1 5 103739DNAArtificial
SequenceSynthetic
373aagatttct 93743PRTArtificial SequenceSynthetic 374Lys Ile Ser
137527DNAArtificial SequenceSynthetic 375atgcaagcta cacaatttcc
gtacact 273769PRTArtificial SequenceSynthetic 376Met Gln Ala Thr
Gln Phe Pro Tyr Thr 1 5377348DNAArtificial SequenceSynthetic
377gaagtgcagc tggtggagtc tgggggagac ttggtacagc ctggcaggtc
cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt
ccggcaagct 120ccagggaggg gcctagagtg ggtctcaggt attacttgga
atagtggtac catggcctat 180gcggactctg tggagggccg attcaccatc
tccagagaca acgccaagaa ctccctgtat 240ctacaaatga acagtctgag
agctgaggac acggccttat attactgtgc aagagaaaac 300tgggcctttg
actactgggg ccagggaacc ctggtcaccg tctcctca 348378116PRTArtificial
SequenceSynthetic 378Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His Trp Val Arg Gln Ala
Pro Gly Arg Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Thr Trp Asn
Ser Gly Thr Met Ala Tyr Ala Asp Ser Val 50 55 60Glu Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Arg
Glu Asn Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105
110Thr Val Ser Ser 115379336DNAArtificial SequenceSynthetic
379gatattgtga tgacccagac tccactctcc tcacctgtca cccttggaca
gccggcctcc 60atctcctgca ggtctagtca cagcctcgta cacagtgatg gaaacaccta
cttgagttgg 120cttcagcaga ggccaggcca gcctccaaga ctcctaattt
ataagatttc taaccggttc 180tctggggtcc cagacagatt cagtggcagt
gggccaggga cagatttcac actgaaaatc 240agcagggtgg aagctgagga
tgtcggggtt tatttctgca tgcaagctac acaatttccg 300tacacttttg
gccaggggac caagctggag atcaaa 336380112PRTArtificial
SequenceSynthetic 380Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser His Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp
Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Pro Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Met Gln Ala 85 90 95Thr Gln
Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105
110381348DNAArtificial SequenceSynthetic 381gaagtgcagc tggtggagtc
tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt
cacctttgat gattatgcca tgcactgggt ccggcaagct 120ccagggaagg
gcctggagtg ggtctcaggt attacttgga atagtggtac catgggctat
180gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa
ctccctgtat 240ctgcaaatga acagtctgag agctgaggac acggccttgt
attactgtgc aagagaaaac 300tgggcctttg actactgggg ccagggaacc
ctggtcaccg tctcctca 348382116PRTArtificial SequenceSynthetic 382Glu
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45 Ser Gly Ile Thr Trp Asn Ser Gly Thr Met Gly Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Arg Glu Asn Trp Ala Phe Asp Tyr
Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser
115383337DNAArtificial SequenceSynthetic 383gatattgtga tgacccagac
tccactctcc tcacctgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca
cagcctcgta cacagtgatg gaaacaccta cttgagttgg 120cttcagcaga
ggccaggcca gcctccaaga ctcctaattt ataagatttc taaccggttc
180tctggggtcc cagacagatt cagtggcagt ggggcaggga cagatttcac
actgaaaatc 240agcagggtgg aagctgagga tgtcggggtt tattactgca
tgcaagctac acaatttccg 300tacacttttg gccaggggac caagctggag atcaaac
337384112PRTArtificial SequenceSynthetic 384Asp Ile Val Met Thr Gln
Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser
Ile Ser Cys Arg Ser Ser His Ser Leu Val His Ser 20 25 30Asp Gly Asn
Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro
Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55
60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65
70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln
Ala 85 90 95Thr Gln Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu
Ile Lys 100 105 110385354DNAArtificial SequenceSynthetic
385gaggtgcaac tggtggagtc tgggggaaac gtggtacggc cgggggggtc
cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatggca tgacctgggt
ccgccaagtt 120ccggggaagg ggctggagtg ggtctctggt attaattgga
atggtggtag tacagattat 180gcagactctg tgaagggccg attcaccata
tctagagaca acgccaagaa ctccctgtat 240ctgcaaatga atagtctgag
agccgaggac acggccttat attactgtgc gagagataag 300gggttctacg
gtatggacgt ctggggccaa gggaccacgg tcaccgtctc ctca
354386118PRTArtificial SequenceSynthetic 386Glu Val Gln Leu Val Glu
Ser Gly Gly Asn Val Val Arg Pro Gly Gly 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Gly Met Thr
Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Asn Trp Asn Gly Gly Ser Thr Asp Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr
Cys 85 90 95Ala Arg Asp Lys Gly Phe Tyr Gly Met Asp Val Trp Gly Gln
Gly Thr 100 105 110Thr Val Thr Val Ser Ser 11538724DNAArtificial
SequenceSynthetic 387ggattcacct ttgatgatta tggc 243888PRTArtificial
SequenceSynthetic 388Gly Phe Thr Phe Asp Asp Tyr Gly 1
538924DNAArtificial SequenceSynthetic 389attaattgga atggtggtag taca
243908PRTArtificial SequenceSynthetic 390Ile Asn Trp Asn Gly Gly
Ser Thr 1 539133DNAArtificial SequenceSynthetic 391gcgagagata
aggggttcta cggtatggac gtc 3339211PRTArtificial SequenceSynthetic
392Ala Arg Asp Lys Gly Phe Tyr Gly Met Asp Val 1 5
10393339DNAArtificial SequenceSynthetic 393gacatcgtga tgacccagtc
tccagactcc ctggctgtgt ctctgggcga gagggccacc 60atcaactgca agtccagcca
gaatccttta tacaactcca acaaaaagaa gtacttagct 120tggtaccagc
agaaaccagg acagccccct aagctggtca tttactgggc atctacccgg
180gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt
cactctcacc 240atcaccagcc tacaggctga agatgtggca gtttattact
gtcaacaata ttatagtact 300ccgtacactt ttggccaggg gaccaagctg gagatcaaa
339394113PRTArtificial SequenceSynthetic 394Asp Ile Val Met Thr Gln
Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15Glu Arg Ala Thr
Ile Asn Cys Lys Ser Ser Gln Asn Pro Leu Tyr Asn 20 25 30Ser Asn Lys
Lys Lys Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro
Pro Lys Leu Val Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55
60Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65
70 75 80Ile Thr Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln
Gln 85 90 95Tyr Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu
Glu Ile 100 105 110Lys39536DNAArtificial SequenceSynthetic
395cagaatcctt tatacaactc caacaaaaag aagtac 3639612PRTArtificial
SequenceSynthetic 396Gln Asn Pro Leu Tyr Asn Ser Asn Lys Lys Lys
Tyr 1 5 103979DNAArtificial SequenceSynthetic 397tgggcatct
93983PRTArtificial SequenceSynthetic 398Trp Ala Ser
139927DNAArtificial SequenceSynthetic 399caacaatatt atagtactcc
gtacact 274009PRTArtificial SequenceSynthetic 400Gln Gln Tyr Tyr
Ser Thr Pro Tyr Thr 1 5401351DNAArtificial SequenceSynthetic
401gaggtgcagc tggtggagtc tgggggaaac gtggtacggc cgggggggtc
cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatggca tgacctgggt
ccgccaagtt 120ccggggaagg ggctggagtg ggtctctggt attaattgga
atggtggtag tacagattat 180gcagactctg tgaagggccg attcaccata
tctagagaca acgccaagaa ctccctgtat 240ctgcaaatga atagtctgag
agccgaggac acggccttat attactgtgc gagagataag 300gggttctacg
gtatggacgt ctggggccaa gggaccacgg tcaccgtctc c
351402117PRTArtificial SequenceSynthetic 402Glu Val Gln Leu Val Glu
Ser Gly Gly Asn Val Val Arg Pro Gly Gly 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Gly Met Thr
Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Asn Trp Asn Gly Gly Ser Thr Asp Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr
Cys 85 90 95Ala Arg Asp Lys Gly Phe Tyr Gly Met Asp Val Trp Gly Gln
Gly Thr 100 105 110Thr Val Thr Val Ser 115403339DNAArtificial
SequenceSynthetic 403gacatcgtga tgacccagtc tccagactcc ctggctgtgt
ctctgggcga gagggccacc 60atcaactgca agtccagcca gaatccttta tacaactcca
acaaaaagaa gtacttagct 120tggtaccagc agaaaccagg acagccccct
aagctggtca tttactgggc atctacccgg 180gaatccgggg tccctgaccg
attcagtggc agcgggtctg ggacagattt cactctcacc 240atcaccagcc
tacaggctga agatgtggca gtttattact gtcaacaata ttatagtact
300ccgtacactt ttggccaggg gaccaagctg gagatcaaa
339404113PRTArtificial SequenceSynthetic 404Asp Ile Val Met Thr Gln
Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15Glu Arg Ala Thr
Ile Asn Cys Lys Ser Ser Gln Asn Pro Leu Tyr Asn 20 25 30Ser Asn Lys
Lys Lys Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro
Pro Lys Leu Val Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55
60Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65
70 75 80Ile Thr Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln
Gln 85 90 95Tyr Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu
Glu Ile 100 105 110Lys405352DNAArtificial SequenceSynthetic
405gaggtgcagc tggtggagtc tgggggaggt gtggtacggc ctggggggtc
cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatggca tgagctgggt
ccgccaagct 120ccagggaagg ggctggagtg ggtctctggt attaattgga
atggtggtag tacaggttat 180gcagactctg tgaagggccg attcaccatc
tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga acagtctgag
agccgaggac acggccttgt atcactgtgc gagagataag 300gggttctacg
gtatggacgt ctggggccaa gggaccacgg tcaccgtctc ct
352406117PRTArtificial SequenceSynthetic 406Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Val Val Arg Pro Gly Gly 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Gly Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Asn Trp Asn Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr His
Cys 85 90 95Ala Arg Asp Lys Gly Phe Tyr Gly Met Asp Val Trp Gly Gln
Gly Thr 100 105 110Thr Val Thr Val Ser 115407340DNAArtificial
SequenceSynthetic 407gacatcgtga tgacccagtc tccagactcc ctggctgtgt
ctctgggcga gagggccacc 60atcaactgca agtccagcca gaatccttta tacaactcca
acaaaaagaa gtacttagct 120tggtaccagc agaaaccagg acagcctcct
aagctgctca tttactgggc atctacccgg 180gaatccgggg tccctgaccg
attcagtggc agcgggtctg ggacagattt cactctcacc 240atcagcagcc
tgcaggctga agatgtggca gtttattact gtcaacaata ttatagtact
300ccgtacactt ttggccaggg gaccaagctg gagatcaaac
340408113PRTArtificial SequenceSynthetic 408Asp Ile Val Met Thr Gln
Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15Glu Arg Ala Thr
Ile Asn Cys Lys Ser Ser Gln Asn Pro Leu Tyr Asn 20 25 30Ser Asn Lys
Lys Lys Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro
Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55
60Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65
70 75 80Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln
Gln 85 90 95Tyr Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu
Glu Ile 100 105 110Lys409384DNAArtificial SequenceSynthetic
409gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc
cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt
ccggcaagct 120ccagggaagg gcctggagtg ggtctcaggt attagttgga
atagtggtag cataggctat 180gcggactctg tgaagggccg attcaccatc
tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga acagtctgag
agctgaggac acggccttgt attactgtgc aaaagataga 300ttccctccgt
ataagtataa cagtggtggt ttttctgatg cttttgaaat ctggggccaa
360gggacaatgg tcaccgtctc ttca 384410128PRTArtificial
SequenceSynthetic 410Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn
Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Lys
Asp Arg Phe Pro Pro Tyr Lys Tyr Asn Ser Gly Gly Phe Ser 100 105
110Asp Ala Phe Glu Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120 12541124DNAArtificial SequenceSynthetic 411ggattcacct
ttgatgatta tgcc 244128PRTArtificial SequenceSynthetic 412Gly Phe
Thr Phe Asp Asp Tyr Ala 1 541324DNAArtificial SequenceSynthetic
413attagttgga atagtggtag cata 244148PRTArtificial SequenceSynthetic
414Ile Ser Trp Asn Ser Gly Ser Ile 1 541563DNAArtificial
SequenceSynthetic 415gcaaaagata gattccctcc gtataagtat aacagtggtg
gtttttctga tgcttttgaa 60atc 6341621PRTArtificial SequenceSynthetic
416Ala Lys Asp Arg Phe Pro Pro Tyr Lys Tyr Asn Ser Gly Gly Phe Ser
1 5 10 15Asp Ala Phe Glu Ile 20417324DNAArtificial
SequenceSynthetic 417gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt
ctccagggga aagagccacc 60ctctcctgca gggccagtca gagttttagc agcagctact
tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat
ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg
gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt
ttgcagtgta ttactgtcag cagtatggta gttcaccgat caccttcggc
300caagggacac gactggagat tgaa 324418108PRTArtificial
SequenceSynthetic 418Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
Ser Leu
Ser Pro Gly 1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln
Ser Phe Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly
Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala
Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp
Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala
Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95Ile Thr Phe Gly
Gln Gly Thr Arg Leu Glu Ile Glu 100 10541921DNAArtificial
SequenceSynthetic 419cagagtttta gcagcagcta c 214207PRTArtificial
SequenceSynthetic 420Gln Ser Phe Ser Ser Ser Tyr 1
54219DNAArtificial SequenceSynthetic 421ggtgcatcc
94223PRTArtificial SequenceSynthetic 422Gly Ala Ser
142327DNAArtificial SequenceSynthetic 423cagcagtatg gtagttcacc
gatcacc 274249PRTArtificial SequenceSynthetic 424Gln Gln Tyr Gly
Ser Ser Pro Ile Thr 1 5425384DNAArtificial SequenceSynthetic
425gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc
cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt
ccggcaagct 120ccagggaagg gcctggagtg ggtctcaggt attagttgga
atagtggtag cataggctat 180gcggactctg tgaagggccg attcaccatc
tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga acagtctgag
agctgaggac acggccttgt attactgtgc aaaagataga 300ttccctccgt
ataagtataa cagtggtggt ttttctgatg cttttgaaat ctggggccaa
360gggacaatgg tcaccgtctc ttca 384426128PRTArtificial
SequenceSynthetic 426Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn
Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Lys
Asp Arg Phe Pro Pro Tyr Lys Tyr Asn Ser Gly Gly Phe Ser 100 105
110Asp Ala Phe Glu Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120 125427324DNAArtificial SequenceSynthetic 427gaaattgtgt
tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca
gggccagtca gagttttagc agcagctact tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac
tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc
tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag
cagtatggta gttcaccgat caccttcggc 300caagggacac gactggagat taaa
324428108PRTArtificial SequenceSynthetic 428Glu Ile Val Leu Thr Gln
Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15Glu Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln Ser Phe Ser Ser Ser 20 25 30Tyr Leu Ala
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55
60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65
70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser
Pro 85 90 95Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100
105429384DNAArtificial SequenceSynthetic 429gaagtgcagc tggtggagtc
tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt
cacctttgat gattatgcca tgcactgggt ccggcaagct 120ccagggaagg
gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat
180gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa
ctccctgtat 240ctgcaaatga acagtctgag agctgaggac acggccttgt
attactgtgc aaaagataga 300ttccctccgt ataagtataa cagtggtggt
ttttctgatg cttttgaaat ctggggccaa 360gggacaatgg tcaccgtctc ttca
384430128PRTArtificial SequenceSynthetic 430Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr
Cys 85 90 95Ala Lys Asp Arg Phe Pro Pro Tyr Lys Tyr Asn Ser Gly Gly
Phe Ser 100 105 110Asp Ala Phe Glu Ile Trp Gly Gln Gly Thr Met Val
Thr Val Ser Ser 115 120 125431325DNAArtificial SequenceSynthetic
431gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga
aagagccacc 60ctctcctgca gggccagtca gagttttagc agcagctact tagcctggta
ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca
gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca
gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta
ttactgtcag cagtatggta gttcaccgat caccttcggc 300caagggacac
gactggagat taaac 325432108PRTArtificial SequenceSynthetic 432Glu
Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Phe Ser Ser Ser
20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu
Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp
Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln
Gln Tyr Gly Ser Ser Pro 85 90 95Ile Thr Phe Gly Gln Gly Thr Arg Leu
Glu Ile Lys 100 105433366DNAArtificial SequenceSynthetic
433gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc
cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctacgaca tgcactgggt
ccgccaagtt 120acaggaaaag gtctggaatg ggtctcagtc attggtactg
ttggtgacac atactatcca 180ggctccctga agggccgatt caccatctcc
agagaaaatg ccaagaactc cttgtatctt 240caaatgaaca ccctgagagc
cggggacacg gctgtttatt actgtgcaag aactggagca 300gcagcccact
cgtactacta cggtatggac gtctggggcc aagggaccat ggtcaccgtc 360tcctca
366434122PRTArtificial SequenceSynthetic 434Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Asp Met His
Trp Val Arg Gln Val Thr Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Val Ile Gly Thr Val Gly Asp Thr Tyr Tyr Pro Gly Ser Leu Lys 50 55
60Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Ser Leu Tyr Leu65
70 75 80Gln Met Asn Thr Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr Cys
Ala 85 90 95Arg Thr Gly Ala Ala Ala His Ser Tyr Tyr Tyr Gly Met Asp
Val Trp 100 105 110Gly Gln Gly Thr Met Val Thr Val Ser Ser 115
12043524DNAArtificial SequenceSynthetic 435ggattcacct tcagtagcta
cgac 244368PRTArtificial SequenceSynthetic 436Gly Phe Thr Phe Ser
Ser Tyr Asp 1 543721DNAArtificial SequenceSynthetic 437attggtactg
ttggtgacac a 214387PRTArtificial SequenceSynthetic 438Ile Gly Thr
Val Gly Asp Thr 1 543948DNAArtificial SequenceSynthetic
439gcaagaactg gagcagcagc ccactcgtac tactacggta tggacgtc
4844016PRTArtificial SequenceSynthetic 440Ala Arg Thr Gly Ala Ala
Ala His Ser Tyr Tyr Tyr Gly Met Asp Val 1 5 10
15441321DNAArtificial SequenceSynthetic 441gaaattgtgt tgacgcagtc
tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca
gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg
ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca
180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag
cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta
gctcacccac tttcggcgga 300gggaccaagg tggagatcaa a
321442107PRTArtificial SequenceSynthetic 442Glu Ile Val Leu Thr Gln
Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15Glu Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55
60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65
70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser
Pro 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100
10544321DNAArtificial SequenceSynthetic 443cagagtgtta gcagcagcta c
214447PRTArtificial SequenceSynthetic 444Gln Ser Val Ser Ser Ser
Tyr 1 54459DNAArtificial SequenceSynthetic 445ggtgcatcc
94463PRTArtificial SequenceSynthetic 446Gly Ala Ser
144724DNAArtificial SequenceSynthetic 447cagcagtatg gtagctcacc cact
244488PRTArtificial SequenceSynthetic 448Gln Gln Tyr Gly Ser Ser
Pro Thr 1 5449363DNAArtificial SequenceSynthetic 449gaggtgcagc
tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag
cctctggatt caccttcagt agctacgaca tgcactgggt ccgccaagtt
120acaggaaaag gtctggaatg ggtctcagtc attggtactg ttggtgacac
atactatcca 180ggctccctga agggccgatt caccatctcc agagaaaatg
ccaagaactc cttgtatctt 240caaatgaaca ccctgagagc cggggacacg
gctgtttatt actgtgcaag aactggagca 300gcagcccact cgtactacta
cggtatggac gtctggggcc aagggaccac ggtcaccgtc 360tcc
363450121PRTArtificial SequenceSynthetic 450Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Asp Met His
Trp Val Arg Gln Val Thr Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Val Ile Gly Thr Val Gly Asp Thr Tyr Tyr Pro Gly Ser Leu Lys 50 55
60Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Ser Leu Tyr Leu65
70 75 80Gln Met Asn Thr Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr Cys
Ala 85 90 95Arg Thr Gly Ala Ala Ala His Ser Tyr Tyr Tyr Gly Met Asp
Val Trp 100 105 110Gly Gln Gly Thr Thr Val Thr Val Ser 115
120451321DNAArtificial SequenceSynthetic 451gaaattgtgt tgacgcagtc
tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca
gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg
ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca
180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag
cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta
gctcacccac tttcggcgga 300gggaccaagg tggagatcaa a
321452107PRTArtificial SequenceSynthetic 452Glu Ile Val Leu Thr Gln
Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15Glu Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55
60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65
70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser
Pro 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100
105453364DNAArtificial SequenceSynthetic 453gaggtgcagc tggtggagtc
tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt
caccttcagt agctacgaca tgcactgggt ccgccaagct 120acaggaaaag
gtctggagtg ggtctcagct attggtactg ttggtgacac atactatcca
180ggctccgtga agggccgatt caccatctcc agagaaaatg ccaagaactc
cttgtatctt 240caaatgaaca gcctgagagc cggggacacg gctgtgtatt
actgtgcaag aactggagca 300gcagcccact cgtactacta cggtatggac
gtctggggcc aagggaccac ggtcaccgtc 360tcct 364454121PRTArtificial
SequenceSynthetic 454Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Asp Met His Trp Val Arg Gln Ala
Thr Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly Thr Val
Gly Asp Thr Tyr Tyr Pro Gly Ser Val Lys 50 55 60Gly Arg Phe Thr Ile
Ser Arg Glu Asn Ala Lys Asn Ser Leu Tyr Leu65 70 75 80Gln Met Asn
Ser Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Thr
Gly Ala Ala Ala His Ser Tyr Tyr Tyr Gly Met Asp Val Trp 100 105
110Gly Gln Gly Thr Thr Val Thr Val Ser 115 120455322DNAArtificial
SequenceSynthetic 455gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt
ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact
tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat
ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg
gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt
ttgcagtgta ttactgtcag cagtatggta gctcacccac tttcggcgga
300gggaccaagg tggagatcaa ac 322456107PRTArtificial
SequenceSynthetic 456Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
Ser Leu Ser Pro Gly 1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala
Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys
Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser
Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly
Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp
Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95Thr Phe
Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105457345DNAArtificial
Sequencesynthetic 457gaggtgcagc tggtggagtc tggggctgag gtgaagaagc
ctggggcctc agtgaaggtc 60tcctgtaagg cttctggatt caccttcacc gactactata
tgcactgggt gcgacaggcc 120cctggacaag ggcttgagtg gctgggatgg
atcaacccta agagtggtgc gacaaagtat 180gcacagaggt ttcagggcag
ggtcaccatg accagggaca cgtccatcag cacagcctac 240atggaactga
acggactaag atctgacgac acggccgttt tttactgtgc gcgaactgat
300gcttttgata tctggggcca agggacaatg gtcaccgtct cttca
345458115PRTArtificial SequenceSynthetic 458Glu Val Gln Leu Val Glu
Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15Ser Val Lys Val
Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30Tyr Met His
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Leu 35 40 45 Gly
Trp Ile Asn Pro Lys Ser Gly Ala Thr Lys Tyr Ala Gln Arg Phe 50 55
60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65
70 75 80Met Glu Leu Asn Gly Leu Arg Ser Asp Asp Thr Ala Val Phe Tyr
Cys 85 90 95Ala Arg Thr Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met
Val Thr 100 105 110Val Ser Ser 11545924DNAArtificial
SequenceSynthetic 459ggattcacct tcaccgacta ctat
244608PRTArtificial SequenceSynthetic 460Gly Phe Thr Phe Thr Asp
Tyr Tyr 1 546124DNAArtificial SequenceSynthetic 461atcaacccta
agagtggtgc gaca 244628PRTArtificial SequenceSynthetic 462Ile Asn
Pro Lys Ser Gly Ala Thr 1 546324DNAArtificial SequenceSynthetic
463gcgcgaactg atgcttttga tatc 244648PRTArtificial SequenceSynthetic
464Ala Arg Thr Asp Ala Phe Asp Ile 1 5465321DNAArtificial
SequenceSynthetic 465gacatccagt tgacccagtc tccttccacc ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgcc gggccagtca gagtgttagt aactggttgg
cctggtatca gcagaaacca 120gggaaagccc ctaaactcct gatctattcg
gcgtctactt tagaaagtgg ggtcccatca 180aggttcagcg gcagtgaatc
tgggacagaa ttcactctca ccatcagcag cctgcagcct 240gatgattttg
caacttatta ctgccaacac tataatagtt attggacgtt cggccaaggg
300accaaggtgg aaatcaaacg a 321466107PRTArtificial SequenceSynthetic
466Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser
Asn Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Thr Leu Glu Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60Ser Glu Ser Gly Thr Glu Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys
Gln His Tyr Asn Ser Tyr Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val
Glu Ile Lys Arg 100 10546718DNAArtificial SequenceSynthetic
467cagagtgtta gtaactgg 184686PRTArtificial SequenceSynthetic 468Gln
Ser Val Ser Asn Trp 1 54699DNAArtificial SequenceSynthetic
469tcggcgtct 94703PRTArtificial SequenceSynthetic 470Ser Ala Ser
147124DNAArtificial SequenceSynthetic 471caacactata atagttattg gacg
244728PRTArtificial SequenceSynthetic 472Gln His Tyr Asn Ser Tyr
Trp Thr 1 5473345DNAArtificial SequenceSynthetic 473caggtgcagc
tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgtaagg
cttctggatt caccttcacc gactactata tgcactgggt gcgacaggcc
120cctggacaag ggcttgagtg gctgggatgg atcaacccta agagtggtgc
gacaaagtat 180gcacagaggt ttcagggcag ggtcaccatg accagggaca
cgtccatcag cacagcctac 240atggaactga acggactaag atctgacgac
acggccgttt tttactgtgc gcgaactgat 300gcttttgata tctggggcca
agggacaatg gtcaccgtct cttca 345474115PRTArtificial
SequenceSynthetic 474Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
Lys Lys Pro Gly Ala 1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser
Gly Phe Thr Phe Thr Asp Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala
Pro Gly Gln Gly Leu Glu Trp Leu 35 40 45 Gly Trp Ile Asn Pro Lys
Ser Gly Ala Thr Lys Tyr Ala Gln Arg Phe 50 55 60Gln Gly Arg Val Thr
Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu
Asn Gly Leu Arg Ser Asp Asp Thr Ala Val Phe Tyr Cys 85 90 95Ala Arg
Thr Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr 100 105
110Val Ser Ser 115475318DNAArtificial SequenceSynthetic
475gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga
cagagtcacc 60atcacttgcc gggccagtca gagtgttagt aactggttgg cctggtatca
gcagaaacca 120gggaaagccc ctaaactcct gatctattcg gcgtctactt
tagaaagtgg ggtcccatca 180aggttcagcg gcagtgaatc tgggacagaa
ttcactctca ccatcagcag cctgcagcct 240gatgattttg caacttatta
ctgccaacac tataatagtt attggacgtt cggccaaggg 300accaaggtgg aaatcaaa
318476106PRTArtificial SequenceSynthetic 476Asp Ile Gln Met Thr Gln
Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Asn Trp 20 25 30Leu Ala Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ser Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60Ser Glu Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr Asn Ser Tyr Trp
Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100
105477345DNAArtificial SequenceSynthetic 477caggtgcagc tggtgcagtc
tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggatt
caccttcacc gactactata tgcactgggt gcgacaggcc 120cctggacaag
ggcttgagtg gatgggatgg atcaacccta agagtggtgc gacaaactat
180gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag
cacagcctac 240atggagctga gcaggctgag atctgacgac acggccgtgt
attactgtgc gcgaactgat 300gcttttgata tctggggcca agggacaatg
gtcaccgtct cttca 345478115PRTArtificial SequenceSynthetic 478Gln
Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10
15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp
Met 35 40 45 Gly Trp Ile Asn Pro Lys Ser Gly Ala Thr Asn Tyr Ala
Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile
Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Thr Asp Ala Phe Asp Ile Trp
Gly Gln Gly Thr Met Val Thr 100 105 110Val Ser Ser
115479319DNAArtificial SequenceSynthetic 479gacatccaga tgacccagtc
tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggccagtca
gagtgttagt aactggttgg cctggtatca gcagaaacca 120gggaaagccc
ctaagctcct gatctattcg gcgtctagtt tagaaagtgg ggtcccatca
180aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag
cctgcagcct 240gatgattttg caacttatta ctgccaacac tataatagtt
attggacgtt cggccaaggg 300accaaggtgg aaatcaaac
319480106PRTArtificial SequenceSynthetic 480Asp Ile Gln Met Thr Gln
Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Asn Trp 20 25 30Leu Ala Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ser Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr Asn Ser Tyr Trp
Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100
105481354DNAArtificial SequenceSynthetic 481gaggtgcagc tggtggagtc
tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt
caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg
ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat
180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa
cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt
attactgtgc gagagatgga 300tatagtggct acgatgacta ctggggccag
ggaaccctgg tcaccgtctc ctca 354482118PRTArtificial SequenceSynthetic
482Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gly Tyr Ser Gly
Tyr Asp Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser
Ser 11548324DNAArtificial SequenceSynthetic 483ggattcacct
tcagtagcta tggc 244848PRTArtificial SequenceSynthetic 484Gly Phe
Thr Phe Ser Ser Tyr Gly 1 548524DNAArtificial SequenceSynthetic
485atatggtatg atggaagtaa taaa 244868PRTArtificial SequenceSynthetic
486Ile Trp Tyr Asp Gly Ser Asn Lys 1 548733DNAArtificial
SequenceSynthetic 487gcgagagatg gatatagtgg ctacgatgac tac
3348811PRTArtificial SequenceSynthetic 488Ala Arg Asp Gly Tyr Ser
Gly Tyr Asp Asp Tyr 1 5 10489321DNAArtificial SequenceSynthetic
489gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga
cagagtcacc 60atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca
gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt
tacaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tggcacagat
ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta
ctgtctacaa gattacaatt accctcggac gttcggccaa 300gggaccaagg
tggaaatcaa a 321490107PRTArtificial SequenceSynthetic 490Asp Ile
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10
15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg
Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln
Asp Tyr Asn Tyr Pro Arg 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu
Ile Lys 100 10549118DNAArtificial SequenceSynthetic 491cagggcatta
gaaatgat 184926PRTArtificial SequenceSynthetic 492Gln Gly Ile Arg
Asn Asp 1 54939DNAArtificial SequenceSynthetic 493gctgcatcc
94943PRTArtificial SequenceSynthetic 494Ala Ala Ser
149527DNAArtificial SequenceSynthetic 495ctacaagatt acaattaccc
tcggacg 274969PRTArtificial SequenceSynthetic 496Leu Gln Asp Tyr
Asn Tyr Pro Arg Thr 1 5497354DNAArtificial SequenceSynthetic
497caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc
cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt
ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg
atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc
tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag
agccgaggac acggctgtgt attactgtgc gagagatgga 300tatagtggct
acgatgacta ctggggccag ggaaccctgg tcaccgtctc ctca
354498118PRTArtificial SequenceSynthetic 498Gln Val Gln Leu Val Glu
Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95Ala Arg Asp Gly Tyr Ser Gly Tyr Asp Asp Tyr Trp Gly Gln
Gly Thr 100 105 110Leu Val Thr Val Ser Ser 115499321DNAArtificial
SequenceSynthetic 499gccatccaga tgacccagtc tccatcctcc ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaga aatgatttag
gctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct
gcatccagtt tacaaagtgg ggtcccatca 180aggttcagcg gcagtggatc
tggcacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg
caacttatta ctgtctacaa gattacaatt accctcggac gttcggccaa
300gggaccaagg tggaaatcaa a 321500107PRTArtificial SequenceSynthetic
500Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg
Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys
Leu Gln Asp Tyr Asn Tyr Pro Arg 85 90 95Thr Phe Gly Gln Gly Thr Lys
Val Glu Ile Lys 100 105501354DNAArtificial SequenceSynthetic
501caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc
cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt
ccgccaggct 120ccaggcaagg ggctagagtg ggtggcagtt atatggtatg
atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc
tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag
agccgaggac acggctgtgt attactgtgc gagagatgga 300tatagtggct
acgatgacta ctggggccag ggaaccctgg tcaccgtctc ctca
354502118PRTArtificial SequenceSynthetic 502Gln Val Gln Leu Val Glu
Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95Ala Arg Asp Gly Tyr Ser Gly Tyr Asp Asp Tyr Trp Gly Gln
Gly Thr 100 105 110Leu Val Thr Val Ser Ser 115503322DNAArtificial
SequenceSynthetic 503gccatccaga tgacccagtc tccatcctcc ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaga aatgatttag
gctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct
gcatccagtt tacaaagtgg ggtcccatca 180aggttcagcg gcagtggatc
tggcacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg
caacttatta ctgtctacaa gattacaatt accctcggac gttcggccaa
300gggaccaagg tggaaatcaa ac 322504107PRTArtificial
SequenceSynthetic 504Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe
Ala Thr Tyr Tyr Cys Leu Gln Asp Tyr Asn Tyr Pro Arg 85 90 95Thr Phe
Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105505348DNAArtificial
SequenceSynthetic 505gaggtgcagc tggtgcagtc tgggggaggc ttggtacagc
ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatgcca
tgcactgggt ccgacaaggt 120ccagggaagg gcctggagtg ggtctcaggt
attagttgga atggtggtag cgcaggctat 180gcggactctg tgaagggccg
attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaattga
acagtctgag agctgaggac acggccttgt attactgtgc aaaagaagac
300tatgcttttg atatctgggg ccaagggaca atggtcaccg tctcctca
348506116PRTArtificial SequenceSynthetic 506Glu Val Gln Leu Val Gln
Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His
Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Ser Trp Asn Gly Gly Ser Ala Gly Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70
75 80Leu Gln Leu Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr
Cys 85 90 95Ala Lys Glu Asp Tyr Ala Phe Asp Ile Trp Gly Gln Gly Thr
Met Val 100 105 110Thr Val Ser Ser 11550724DNAArtificial
SequenceSynthetic 507ggattcacct ttgatgatta tgcc 245088PRTArtificial
SequenceSynthetic 508Gly Phe Thr Phe Asp Asp Tyr Ala 1
550924DNAArtificial SequenceSynthetic 509attagttgga atggtggtag cgca
245108PRTArtificial SequenceSynthetic 510Ile Ser Trp Asn Gly Gly
Ser Ala 1 551127DNAArtificial SequenceSynthetic 511gcaaaagaag
actatgcttt tgatatc 275129PRTArtificial SequenceSynthetic 512Ala Lys
Glu Asp Tyr Ala Phe Asp Ile 1 5513336DNAArtificial
SequenceSynthetic 513gacatcgtga tgacccagac tccactctcc tcacctgtca
cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgta cacagtgatg
gaaacaccta cttgagttgg 120cttcagcaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgaaaatc 240agcagggtgg
aagctgagga tgtcggggtt tattactgca tgcaagctac acaatttccg
300tacacttttg gccaggggac caaggtggag atcaaa 336514112PRTArtificial
SequenceSynthetic 514Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp
Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln
Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105
11051533DNAArtificial SequenceSynthetic 515caaagcctcg tacacagtga
tggaaacacc tac 3351611PRTArtificial SequenceSynthetic 516Gln Ser
Leu Val His Ser Asp Gly Asn Thr Tyr 1 5 105179DNAArtificial
SequenceSynthetic 517aagatttct 95183PRTArtificial SequenceSynthetic
518Lys Ile Ser 151927DNAArtificial SequenceSynthetic 519atgcaagcta
cacaatttcc gtacact 275209PRTArtificial SequenceSynthetic 520Met Gln
Ala Thr Gln Phe Pro Tyr Thr 1 5521348DNAArtificial
SequenceSynthetic 521gaagtgcagc tggtggagtc tgggggaggc ttggtacagc
ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt cacctttgat gattatgcca
tgcactgggt ccgacaaggt 120ccagggaagg gcctggagtg ggtctcaggt
attagttgga atggtggtag cgcaggctat 180gcggactctg tgaagggccg
attcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaattga
acagtctgag agctgaggac acggccttgt attactgtgc aaaagaagac
300tatgcttttg atatctgggg ccaagggaca atggtcaccg tctcttca
348522116PRTArtificial SequenceSynthetic 522Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His
Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Ser Trp Asn Gly Gly Ser Ala Gly Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Leu Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr
Cys 85 90 95Ala Lys Glu Asp Tyr Ala Phe Asp Ile Trp Gly Gln Gly Thr
Met Val 100 105 110Thr Val Ser Ser 115523336DNAArtificial
SequenceSynthetic 523gatattgtga tgacccagac tccactctcc tcacctgtca
cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgta cacagtgatg
gaaacaccta cttgagttgg 120cttcagcaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgaaaatc 240agcagggtgg
aagctgagga tgtcggggtt tattactgca tgcaagctac acaatttccg
300tacacttttg gccaggggac caagctggag atcaaa 336524112PRTArtificial
SequenceSynthetic 524Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp
Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln
Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105
110525348DNAArtificial SequenceSynthetic 525gaagtgcagc tggtggagtc
tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt
cacctttgat gattatgcca tgcactgggt ccggcaagct 120ccagggaagg
gcctggagtg ggtctcaggt attagttgga atggtggtag cgcaggctat
180gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa
ctccctgtat 240ctgcaaatga acagtctgag agctgaggac acggccttgt
attactgtgc aaaagaagac 300tatgcttttg atatctgggg ccaagggaca
atggtcaccg tctcttca 348526116PRTArtificial SequenceSynthetic 526Glu
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45 Ser Gly Ile Ser Trp Asn Gly Gly Ser Ala Gly Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Lys Glu Asp Tyr Ala Phe Asp Ile
Trp Gly Gln Gly Thr Met Val 100 105 110Thr Val Ser Ser
115527337DNAArtificial SequenceSynthetic 527gatattgtga tgacccagac
tccactctcc tcacctgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca
aagcctcgta cacagtgatg gaaacaccta cttgagttgg 120cttcagcaga
ggccaggcca gcctccaaga ctcctaattt ataagatttc taaccggttc
180tctggggtcc cagacagatt cagtggcagt ggggcaggga cagatttcac
actgaaaatc 240agcagggtgg aagctgagga tgtcggggtt tattactgca
tgcaagctac acaatttccg 300tacacttttg gccaggggac caagctggag atcaaac
337528112PRTArtificial SequenceSynthetic 528Asp Ile Val Met Thr Gln
Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser
Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn
Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro
Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55
60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65
70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln
Ala 85 90 95Thr Gln Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu
Ile Lys 100 105 110529348DNAArtificial SequenceSynthetic
529gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc
cctgagactc 60tcctgtgcag cctctggatt cacctttgaa gattatgcca tgcactgggt
ccggcaagct 120ccagggaagg gcctggaatg ggtctcaggt attacttgga
atagtgataa taaaggctat 180gcggactctg tgaagggccg attcaccatc
tccagagaca acgccaagta ctccctgtat 240ctgcaaatga acagtctgag
agctgaggac acggccttgt attactgtgc aaaagaggac 300tgggcgtttg
actactgggg ccagggaacc ctggtcaccg tctcctca 348530116PRTArtificial
SequenceSynthetic 530Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Glu Asp Tyr 20 25 30Ala Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Thr Trp Asn
Ser Asp Asn Lys Gly Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ala Lys Tyr Ser Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Lys
Glu Asp Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105
110Thr Val Ser Ser 11553124DNAArtificial SequenceSynthetic
531ggattcacct ttgaagatta tgcc 245328PRTArtificial SequenceSynthetic
532Gly Phe Thr Phe Glu Asp Tyr Ala 1 553324DNAArtificial
SequenceSynthetic 533attacttgga atagtgataa taaa 245348PRTArtificial
SequenceSynthetic 534Ile Thr Trp Asn Ser Asp Asn Lys 1
553527DNAArtificial SequenceSynthetic 535gcaaaagagg actgggcgtt
tgactac 275369PRTArtificial SequenceSynthetic 536Ala Lys Glu Asp
Trp Ala Phe Asp Tyr 1 5537321DNAArtificial SequenceSynthetic
537gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga
cagagtcacc 60atcacttgtc gtgcgagtca gggtattaac agttggttag cctggtatca
gcagaaacca 120gggaaagccc ctaagctcct gatctacgct gcatccagtt
tgcagagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat
ttcactctca ccatcagcgg cctccagcct 240gaagattttg caacttacta
ttgtcaacag gctaacagtt tcccgtacac ttttggccag 300gggaccaagg
tggaaatcaa a 321538107PRTArtificial SequenceSynthetic 538Asp Ile
Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10
15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Asn Ser Trp
20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg
Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
Gly Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
Ala Asn Ser Phe Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu
Ile Lys 100 10553918DNAArtificial SequenceSynthetic 539cagggtatta
acagttgg 185406PRTArtificial SequenceSynthetic 540Gln Gly Ile Asn
Ser Trp 1 55419DNAArtificial SequenceSynthetic 541gctgcatcc
95423PRTArtificial SequenceSynthetic 542Ala Ala Ser
154327DNAArtificial SequenceSynthetic 543caacaggcta acagtttccc
gtacact 275449PRTArtificial SequenceSynthetic 544Gln Gln Ala Asn
Ser Phe Pro Tyr Thr 1 5545348DNAArtificial SequenceSynthetic
545gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc
cctgagactc 60tcctgtgcag cctctggatt cacctttgaa gattatgcca tgcactgggt
ccggcaagct 120ccagggaagg gcctggaatg ggtctcaggt attacttgga
atagtgataa taaaggctat 180gcggactctg tgaagggccg attcaccatc
tccagagaca acgccaagta ctccctgtat 240ctgcaaatga acagtctgag
agctgaggac acggccttgt attactgtgc aaaagaggac 300tgggcgtttg
actactgggg ccagggaacc ctggtcaccg tctcctca 348546116PRTArtificial
SequenceSynthetic 546Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Glu Asp Tyr 20 25 30Ala Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Thr Trp Asn
Ser Asp Asn Lys Gly Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ala Lys Tyr Ser Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Lys
Glu Asp Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105
110Thr Val Ser Ser 115547321DNAArtificial SequenceSynthetic
547gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga
cagagtcacc 60atcacttgtc gtgcgagtca gggtattaac agttggttag cctggtatca
gcagaaacca 120gggaaagccc ctaagctcct gatctacgct gcatccagtt
tgcagagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat
ttcactctca ccatcagcgg cctccagcct 240gaagattttg caacttacta
ttgtcaacag gctaacagtt tcccgtacac ttttggccag 300gggaccaagc
tggagatcaa a 321548107PRTArtificial SequenceSynthetic 548Asp Ile
Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10
15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Asn Ser Trp
20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg
Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
Gly Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
Ala Asn Ser Phe Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Leu Glu
Ile Lys 100 105549348DNAArtificial SequenceSynthetic 549gaagtgcagc
tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60tcctgtgcag
cctctggatt cacctttgaa gattatgcca tgcactgggt ccggcaagct
120ccagggaagg gcctggagtg ggtctcaggt attacttgga atagtgataa
taaaggctat 180gcggactctg tgaagggccg attcaccatc tccagagaca
acgccaagaa ctccctgtat 240ctgcaaatga acagtctgag agctgaggac
acggccttgt attactgtgc aaaagaggac 300tgggcgtttg actactgggg
ccagggaacc ctggtcaccg tctcctca 348550116PRTArtificial
SequenceSynthetic 550Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Glu Asp Tyr 20 25 30Ala Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Thr Trp Asn
Ser Asp Asn Lys Gly Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Lys
Glu Asp Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105
110Thr Val Ser Ser 115551322DNAArtificial SequenceSynthetic
551gacatccaga tgacccagtc tccatcttct gtgtctgcat ctgtaggaga
cagagtcacc 60atcacttgtc gggcgagtca gggtattaac agttggttag cctggtatca
gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt
tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat
ttcactctca ctatcagcag cctgcagcct 240gaagattttg caacttacta
ttgtcaacag gctaacagtt tcccgtacac ttttggccag 300gggaccaagc
tggagatcaa ac 322552107PRT`Artificial SequenceSynthetic 552Asp Ile
Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10
15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Asn Ser Trp
20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg
Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
Ala Asn Ser Phe Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Leu Glu
Ile Lys 100 105553348DNAArtificial SequenceSynthetic 553gaggtgcagc
tggtgcagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60tcctgtgcag
cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct
120ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag
caaaggctat 180gcggactctg tgaagggccg attcaccatc tccagagaca
acgccaagaa ctccctgtat 240ctgcaaatga acagtctgag acgtgaggac
acggccttgt attactgtgt aaaagaggac 300tgggcgtttg actactgggg
ccagggaacc ctggtcaccg tctcctca 348554116PRTArtificial
SequenceSynthetic 554Glu Val Gln Leu Val Gln Ser
Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly
Ile Ser Trp Asn Ser Gly Ser Lys Gly Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Arg Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95Val Lys Glu Asp Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu
Val 100 105 110Thr Val Ser Ser 11555524DNAArtificial
SequenceSynthetic 555ggattcacct ttgatgatta tgcc 245568PRTArtificial
SequenceSynthetic 556Gly Phe Thr Phe Asp Asp Tyr Ala 1
555724DNAArtificial SequenceSynthetic 557attagttgga atagtggtag caaa
245588PRTArtificial SequenceSynthetic 558Ile Ser Trp Asn Ser Gly
Ser Lys 1 555927DNAArtificial SequenceSynthetic 559gtaaaagagg
actgggcgtt tgactac 275609PRTArtificial SequenceSynthetic 560Val Lys
Glu Asp Trp Ala Phe Asp Tyr 1 5561315DNAArtificial
SequenceSynthetic 561gacatccaga tgacccagtc tccatcctcc ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgcc aggcgagtca ggacattagc aactatttaa
attggtatca acaaaaacca 120gggaaagccc ctaagttcct gatctacgat
gcatccaatt tgggaacagg ggtcccatca 180aggttcagtg gaagtggatc
tgggacagat tttactttca ccatcagcag cctgcagcct 240gaagatattg
cgacatatta ctgtcaacag tatgataatc tccctttcgg cggagggacc
300aaggtggaaa tcaaa 315562105PRTArtificial SequenceSynthetic 562Asp
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10
15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Phe Leu
Ile 35 40 45 Tyr Asp Ala Ser Asn Leu Gly Thr Gly Val Pro Ser Arg
Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser
Ser Leu Gln Pro65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln
Tyr Asp Asn Leu Pro Phe 85 90 95Gly Gly Gly Thr Lys Val Glu Ile Lys
100 10556318DNAArtificial SequenceSynthetic 563caggacatta gcaactat
185646PRTArtificial SequenceSynthetic 564Gln Asp Ile Ser Asn Tyr 1
55659DNAArtificial SequenceSynthetic 565gatgcatcc
95663PRTArtificial SequenceSynthetic 566Asp Ala Ser
156721DNAArtificial SequenceSynthetic 567caacagtatg ataatctccc t
215687PRTArtificial SequenceSynthetic 568Gln Gln Tyr Asp Asn Leu
Pro 1 5569348DNAArtificial SequenceSynthetic 569gaagtgcagc
tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60tcctgtgcag
cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct
120ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag
caaaggctat 180gcggactctg tgaagggccg attcaccatc tccagagaca
acgccaagaa ctccctgtat 240ctgcaaatga acagtctgag acgtgaggac
acggccttgt attactgtgt aaaagaggac 300tgggcgtttg actactgggg
ccagggaacc ctggtcaccg tctcctca 348570116PRTArtificial
SequenceSynthetic 570Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn
Ser Gly Ser Lys Gly Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Arg Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95Val Lys
Glu Asp Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105
110Thr Val Ser Ser 115571315DNAArtificial SequenceSynthetic
571gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga
cagagtcacc 60atcacttgcc aggcgagtca ggacattagc aactatttaa attggtatca
acaaaaacca 120gggaaagccc ctaagttcct gatctacgat gcatccaatt
tgggaacagg ggtcccatca 180aggttcagtg gaagtggatc tgggacagat
tttactttca ccatcagcag cctgcagcct 240gaagatattg cgacatatta
ctgtcaacag tatgataatc tccctttcgg cggagggacc 300aaggtggaga tcaaa
315572105PRTArtificial SequenceSynthetic 572Asp Ile Gln Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr
Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Phe Leu Ile 35 40 45 Tyr
Asp Ala Ser Asn Leu Gly Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55
60Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro
Phe 85 90 95Gly Gly Gly Thr Lys Val Glu Ile Lys 100
105573348DNAArtificial SequenceSynthetic 573gaagtgcagc tggtggagtc
tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60tcctgtgcag cctctggatt
cacctttgat gattatgcca tgcactgggt ccggcaagct 120ccagggaagg
gcctggagtg ggtctcaggt attagttgga atagtggtag caaaggctat
180gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa
ctccctgtat 240ctgcaaatga acagtctgag agctgaggac acggccttgt
attactgtgt aaaagaggac 300tgggcgtttg actactgggg ccagggaacc
ctggtcaccg tctcctca 348574116PRTArtificial SequenceSynthetic 574Glu
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Lys Gly Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Leu Tyr Tyr Cys 85 90 95Val Lys Glu Asp Trp Ala Phe Asp Tyr
Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser
115575316DNAArtificial SequenceSynthetic 575gacatccaga tgacccagtc
tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc aggcgagtca
ggacattagc aactatttaa attggtatca gcagaaacca 120gggaaagccc
ctaagctcct gatctacgat gcatccaatt tggaaacagg ggtcccatca
180aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag
cctgcagcct 240gaagatattg caacatatta ctgtcaacag tatgataatc
tccctttcgg cggagggacc 300aaggtggaga tcaaac 316576105PRTArtificial
SequenceSynthetic 576Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala
Ser Gln Asp Ile Ser Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Leu
Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr
Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Ile
Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Phe 85 90 95Gly Gly
Gly Thr Lys Val Glu Ile Lys 100 105577375DNAArtificial
SequenceSynthetic 577caggtgcagc tggtgcagtc aggtccagga ctggtgaagc
cctcgcagac cctctcactc 60acctgtgcca tctccgggga cagtgtctct agcaacagtg
ctgcttggaa ctggatcagg 120cagtccccat cgagaggcct tgagtggctg
ggaaggacat actacaggtc caagtggtat 180aatgattatg cagtatctgt
gaaaagtcga ataaccatca acccagacac atccaagaac 240cagttctccc
tgcagctgaa ctctgtgact cccgaggaca cggctgtgta ttactgtgca
300agagggtata gcagcagctg gtacgggggt gcttttgata tctggggcca
agggacaatg 360gtcaccgtct cttca 375578125PRTArtificial
SequenceSynthetic 578Gln Val Gln Leu Val Gln Ser Gly Pro Gly Leu
Val Lys Pro Ser Gln 1 5 10 15Thr Leu Ser Leu Thr Cys Ala Ile Ser
Gly Asp Ser Val Ser Ser Asn 20 25 30Ser Ala Ala Trp Asn Trp Ile Arg
Gln Ser Pro Ser Arg Gly Leu Glu 35 40 45 Trp Leu Gly Arg Thr Tyr
Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala 50 55 60Val Ser Val Lys Ser
Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn65 70 75 80Gln Phe Ser
Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val 85 90 95Tyr Tyr
Cys Ala Arg Gly Tyr Ser Ser Ser Trp Tyr Gly Gly Ala Phe 100 105
110Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120
12557930DNAArtificial SequenceSynthetic 579ggggacagtg tctctagcaa
cagtgctgct 3058010PRTArtificial SequenceSynthetic 580Gly Asp Ser
Val Ser Ser Asn Ser Ala Ala 1 5 1058127DNAArtificial
SequenceSynthetic 581acatactaca ggtccaagtg gtataat
275829PRTArtificial SequenceSynthetic 582Thr Tyr Tyr Arg Ser Lys
Trp Tyr Asn 1 558345DNAArtificial SequenceSynthetic 583gcaagagggt
atagcagcag ctggtacggg ggtgcttttg atatc 4558415PRTArtificial
SequenceSynthetic 584Ala Arg Gly Tyr Ser Ser Ser Trp Tyr Gly Gly
Ala Phe Asp Ile 1 5 10 15585321DNAArtificial SequenceSynthetic
585gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga
cagagtcacc 60atcacttgcc gggcaagtca gagcattagc agttatttaa gttggtatca
gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccagtt
tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat
ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta
ctgtcaacag agttacagta ccccattcac tttcggccct 300gggaccaagg
tggaaatcaa a 321586107PRTArtificial SequenceSynthetic 586Asp Ile
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10
15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg
Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
Ser Tyr Ser Thr Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Glu
Ile Lys 100 10558718DNAArtificial SequenceSynthetic 587cagagcatta
gcagttat 185886PRTArtificial SequenceSynthetic 588Gln Ser Ile Ser
Ser Tyr 1 55899DNAArtificial SequenceSynthetic 589gctgcatcc
95903PRTArtificial SequenceSynthetic 590Ala Ala Ser
159127DNAArtificial SequenceSynthetic 591caacagagtt acagtacccc
attcact 275929PRTArtificial SequenceSynthetic 592Gln Gln Ser Tyr
Ser Thr Pro Phe Thr 1 5593375DNAArtificial SequenceSynthetic
593caggtacagc tgcagcagtc aggtccagga ctggtgaagc cctcgcagac
cctctcactc 60acctgtgcca tctccgggga cagtgtctct agcaacagtg ctgcttggaa
ctggatcagg 120cagtccccat cgagaggcct tgagtggctg ggaaggacat
actacaggtc caagtggtat 180aatgattatg cagtatctgt gaaaagtcga
ataaccatca acccagacac atccaagaac 240cagttctccc tgcagctgaa
ctctgtgact cccgaggaca cggctgtgta ttactgtgca 300agagggtata
gcagcagctg gtacgggggt gcttttgata tctggggcca agggacaatg
360gtcaccgtct cttca 375594125PRTArtificial SequenceSynthetic 594Gln
Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10
15Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn
20 25 30Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu
Glu 35 40 45 Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn
Asp Tyr Ala 50 55 60Val Ser Val Lys Ser Arg Ile Thr Ile Asn Pro Asp
Thr Ser Lys Asn65 70 75 80Gln Phe Ser Leu Gln Leu Asn Ser Val Thr
Pro Glu Asp Thr Ala Val 85 90 95Tyr Tyr Cys Ala Arg Gly Tyr Ser Ser
Ser Trp Tyr Gly Gly Ala Phe 100 105 110Asp Ile Trp Gly Gln Gly Thr
Met Val Thr Val Ser Ser 115 120 125595321DNAArtificial
SequenceSynthetic 595gacatccaga tgacccagtc tccatcctcc ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattagc agttatttaa
gttggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct
gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc
tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg
caacttacta ctgtcaacag agttacagta ccccattcac tttcggccct
300gggaccaaag tggatatcaa a 321596107PRTArtificial SequenceSynthetic
596Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser
Ser Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys
Gln Gln Ser Tyr Ser Thr Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys
Val Asp Ile Lys 100 105597375DNAArtificial SequenceSynthetic
597caggtacagc tgcagcagtc aggtccagga ctggtgaagc cctcgcagac
cctctcactc 60acctgtgcca tctccgggga cagtgtctct agcaacagtg ctgcttggaa
ctggatcagg 120cagtccccat cgagaggcct tgagtggctg ggaaggacat
actacaggtc caagtggtat 180aatgattatg cagtatctgt gaaaagtcga
ataaccatca acccagacac atccaagaac 240cagttctccc tgcagctgaa
ctctgtgact cccgaggaca cggctgtgta ttactgtgca 300agagggtata
gcagcagctg gtacgggggt gcttttgata tctggggcca agggacaatg
360gtcaccgtct cttca 375598125PRTArtificial SequenceSynthetic 598Gln
Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10
15Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn
20 25 30Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu
Glu 35 40 45 Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn
Asp Tyr Ala 50 55 60Val Ser Val Lys Ser Arg Ile Thr Ile Asn Pro Asp
Thr Ser Lys Asn65 70 75 80Gln Phe Ser Leu Gln Leu Asn Ser Val Thr
Pro Glu Asp Thr Ala Val 85 90 95Tyr Tyr Cys Ala Arg Gly Tyr Ser Ser
Ser Trp Tyr Gly Gly Ala Phe 100 105 110Asp Ile Trp Gly Gln Gly Thr
Met Val Thr Val Ser Ser 115 120 125599322DNAArtificial
SequenceSynthetic 599gacatccaga tgacccagtc tccatcctcc ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattagc agttatttaa
attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct
gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc
tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg
caacttacta ctgtcaacag agttacagta ccccattcac tttcggccct
300gggaccaaag tggatatcaa ac 322600107PRTArtificial
SequenceSynthetic 600Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75
80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Phe
85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100
105601357DNAArtificial SequenceSynthetic 601caggtgcagc tgcaggagtc
tgggggaggc tcggtacagc ctggggggtc cctgcgactc 60tcctgtgcaa cctctggatt
cacctttacc aactttgcca taagctgggt ccgccaggct 120ccaggcagtg
ggctggagtg ggtctcatct attactggta gtggtgatta cgcatactac
180gcagactccg tgaagggccg gttcaccatc tccagagaca gttccaagaa
cacgctctat 240ctacaaatga acagcctgag agccgacgac acggccgtat
atttctgtac gagagaagac 300tatattaact cgtcctttga ctactggggc
cagggaacca cggtcaccgt ctcctca 357602119PRTArtificial
SequenceSynthetic 602Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser
Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Thr Ser
Gly Phe Thr Phe Thr Asn Phe 20 25 30Ala Ile Ser Trp Val Arg Gln Ala
Pro Gly Ser Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Thr Gly Ser
Gly Asp Tyr Ala Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Ser Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95Thr Arg
Glu Asp Tyr Ile Asn Ser Ser Phe Asp Tyr Trp Gly Gln Gly 100 105
110Thr Thr Val Thr Val Ser Ser 11560324DNAArtificial
SequenceSynthetic 603ggattcacct ttaccaactt tgcc 246048PRTArtificial
SequenceSynthetic 604Gly Phe Thr Phe Thr Asn Phe Ala 1
560524DNAArtificial SequenceSynthetic 605attactggta gtggtgatta cgca
246068PRTArtificial SequenceSynthetic 606Ile Thr Gly Ser Gly Asp
Tyr Ala 1 560736DNAArtificial SequenceSynthetic 607acgagagaag
actatattaa ctcgtccttt gactac 3660812PRTArtificial SequenceSynthetic
608Thr Arg Glu Asp Tyr Ile Asn Ser Ser Phe Asp Tyr 1 5
10609333DNAArtificial SequenceSynthetic 609gacatccaga tgacccagac
tccactctcc tcacctgtca cccttggaca gccggcctcc 60atctcctgta ggtctagtca
gagcctcgta cacagtgatg gaaataccta cttgagttgg 120cttcagcgga
ggccaggcca gcctccaaga ctcctaattt ataagatttc taaccggttc
180tctggggtcc cagacagatt cagtggcagt ggggcaggga cagatttcac
actgaaaatc 240agcagggtgg aagctgagga tgtcggggtt tattactgca
tgcaagctac acaacttccg 300acgttcggcc aagggaccaa ggtggaaatc aaa
333610111PRTArtificial SequenceSynthetic 610Asp Ile Gln Met Thr Gln
Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser
Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn
Thr Tyr Leu Ser Trp Leu Gln Arg Arg Pro Gly Gln Pro 35 40 45 Pro
Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55
60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65
70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln
Ala 85 90 95Thr Gln Leu Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
Lys 100 105 11061133DNAArtificial SequenceSynthetic 611cagagcctcg
tacacagtga tggaaatacc tac 3361211PRTArtificial SequenceSynthetic
612Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr 1 5
106139DNAArtificial SequenceSynthetic 613aagatttct
96143PRTArtificial SequenceSynthetic 614Lys Ile Ser
161524DNAArtificial SequenceSynthetic 615atgcaagcta cacaacttcc gacg
246168PRTArtificial SequenceSynthetic 616Met Gln Ala Thr Gln Leu
Pro Thr 1 5617357DNAArtificial SequenceSynthetic 617gaggtgcagc
tgttggagtc tgggggaggc tcggtacagc ctggggggtc cctgcgactc 60tcctgtgcaa
cctctggatt cacctttacc aactttgcca taagctgggt ccgccaggct
120ccaggcagtg ggctggagtg ggtctcatct attactggta gtggtgatta
cgcatactac 180gcagactccg tgaagggccg gttcaccatc tccagagaca
gttccaagaa cacgctctat 240ctacaaatga acagcctgag agccgacgac
acggccgtat atttctgtac gagagaagac 300tatattaact cgtcctttga
ctactggggc cagggaaccc tggtcaccgt ctcctca 357618119PRTArtificial
SequenceSynthetic 618Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Ser
Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Thr Ser
Gly Phe Thr Phe Thr Asn Phe 20 25 30Ala Ile Ser Trp Val Arg Gln Ala
Pro Gly Ser Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Thr Gly Ser
Gly Asp Tyr Ala Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Ser Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95Thr Arg
Glu Asp Tyr Ile Asn Ser Ser Phe Asp Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 115619333DNAArtificial
SequenceSynthetic 619gatattgtga tgacccagac tccactctcc tcacctgtca
cccttggaca gccggcctcc 60atctcctgta ggtctagtca gagcctcgta cacagtgatg
gaaataccta cttgagttgg 120cttcagcgga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgaaaatc 240agcagggtgg
aagctgagga tgtcggggtt tattactgca tgcaagctac acaacttccg
300acgttcggcc aagggaccaa ggtggaaatc aaa 333620111PRTArtificial
SequenceSynthetic 620Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp
Leu Gln Arg Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln
Leu Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105
110621357DNAArtificial SequenceSynthetic 621gaggtgcagc tgttggagtc
tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt
cacctttacc aactttgcca tgagctgggt ccgccaggct 120ccagggaagg
ggctggagtg ggtctcagct attactggta gtggtgatta cgcatactac
180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa
cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat
attactgtac gagagaagac 300tatattaact cgtcctttga ctactggggc
cagggaaccc tggtcaccgt ctcctca 357622119PRTArtificial
SequenceSynthetic 622Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Gly 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Thr Asn Phe 20 25 30Ala Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Gly Ser
Gly Asp Tyr Ala Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Thr Arg
Glu Asp Tyr Ile Asn Ser Ser Phe Asp Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 115623334DNAArtificial
SequenceSynthetic 623gatattgtga tgacccagac tccactctcc tcacctgtca
cccttggaca gccggcctcc 60atctcctgca ggtctagtca gagcctcgta cacagtgatg
gaaataccta cttgagttgg 120cttcagcaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgaaaatc 240agcagggtgg
aagctgagga tgtcggggtt tattactgca tgcaagctac acaacttccg
300acgttcggcc aagggaccaa ggtggaaatc aaac 334624111PRTArtificial
SequenceSynthetic 624Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp
Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln
Leu Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105
110625357DNAArtificial SequenceSynthetic 625caggtgcagc tggtggagtc
tgggggaggc gtggtccagc ctgggatgtc cctgagactc 60tcctgtgcag cgtccggatt
taccttcagg agatatggca tgcactgggt ccgccaggct 120ccaggcaagg
ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatattat
180gtagattccg tgaagggccg attcaccatc tccagagaca attccaagaa
cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt
attactgtgc gagcgaaatt 300acagttgggg actggttcga cccctggggc
cagggaaccc tggtcaccgt ctcctca 357626119PRTArtificial
SequenceSynthetic 626Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
Val Gln Pro Gly Met 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Arg Arg Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp
Gly Ser Asn Lys Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Ser
Glu Ile Thr Val Gly Asp Trp Phe Asp Pro Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 11562724DNAArtificial
SequenceSynthetic 627ggatttacct tcaggagata tggc 246288PRTArtificial
SequenceSynthetic 628Gly Phe Thr Phe Arg Arg Tyr Gly 1
562924DNAArtificial SequenceSynthetic 629atatggtatg atggaagtaa taaa
246308PRTArtificial SequenceSynthetic 630Ile Trp Tyr Asp Gly Ser
Asn Lys 1 563136DNAArtificial SequenceSynthetic 631gcgagcgaaa
ttacagttgg ggactggttc gacccc 3663212PRTArtificial SequenceSynthetic
632Ala Ser Glu Ile Thr Val Gly Asp Trp Phe Asp Pro 1 5
10633321DNAArtificial SequenceSynthetic 633gacatccaga tgacccagtc
tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcaagtca
gggcattaga aatgatttag gctggtatca gcagaaacca 120gggaaagccc
ctaaactcct gatctatgct gcatccagtt tacacagtgg ggtcccatca
180aggttcagcg gcagtggatc tggcacagat ttcactctca ccatcagcag
cctgcagcct 240gaagattttg caacttatta ctgtctacag gatttcaatt
accctctcac tttcggcgga 300gggaccaagg tggagatcaa a
321634107PRTArtificial SequenceSynthetic 634Asp Ile Gln Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Phe Asn Tyr Pro
Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100
10563518DNAArtificial SequenceSynthetic 635cagggcatta gaaatgat
186366PRTArtificial SequenceSynthetic 636Gln Gly Ile Arg Asn Asp 1
56379DNAArtificial SequenceSynthetic 637gctgcatcc
96383PRTArtificial SequenceSynthetic 638Ala Ala Ser
163927DNAArtificial SequenceSynthetic 639ctacaggatt tcaattaccc
tctcact 276409PRTArtificial SequenceSynthetic 640Leu Gln Asp Phe
Asn Tyr Pro Leu Thr 1 5641357DNAArtificial SequenceSynthetic
641caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggatgtc
cctgagactc 60tcctgtgcag cgtccggatt taccttcagg agatatggca tgcactgggt
ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg
atggaagtaa taaatattat 180gtagattccg tgaagggccg attcaccatc
tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag
agccgaggac acggctgtgt attactgtgc gagcgaaatt 300acagttgggg
actggttcga cccctggggc cagggaaccc tggtcaccgt ctcctca
357642119PRTArtificial SequenceSynthetic 642Gln Val Gln Leu Val Glu
Ser Gly Gly Gly Val Val Gln Pro Gly Met 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Arg Tyr 20 25 30Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Val Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95Ala Ser Glu Ile Thr Val Gly Asp Trp Phe Asp Pro Trp Gly
Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser
115643321DNAArtificial SequenceSynthetic 643gccatccaga tgacccagtc
tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcaagtca
gggcattaga aatgatttag gctggtatca gcagaaacca 120gggaaagccc
ctaaactcct gatctatgct gcatccagtt tacacagtgg ggtcccatca
180aggttcagcg gcagtggatc tggcacagat ttcactctca ccatcagcag
cctgcagcct 240gaagattttg caacttatta ctgtctacag gatttcaatt
accctctcac tttcggcgga 300gggaccaagg tggagatcaa a
321644107PRTArtificial SequenceSynthetic 644Ala Ile Gln Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Phe Asn Tyr Pro
Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100
105645357DNAArtificial SequenceSynthetic 645caggtgcagc tggtggagtc
tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt
taccttcagg agatatggca tgcactgggt ccgccaggct 120ccaggcaagg
ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat
180gcagactccg tgaagggccg attcaccatc tccagagaca actccaagaa
cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt
attactgtgc gagcgaaatt 300acagttgggg actggttcga cccctggggc
cagggaaccc tggtcaccgt ctcctca 357646119PRTArtificial
SequenceSynthetic 646Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Arg Arg Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp
Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Ser
Glu Ile Thr Val Gly Asp Trp Phe Asp Pro Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 115647322DNAArtificial
SequenceSynthetic 647gccatccaga tgacccagtc tccatcctcc ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaga aatgatttag
gctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct
gcatccagtt tacaaagtgg ggtcccatca 180aggttcagcg gcagtggatc
tggcacagat ttcactctca ccatcagcag cctgcagcct
240gaagattttg caacttatta ctgtctacag gatttcaatt accctctcac
tttcggcgga 300gggaccaagg tggagatcaa ac 322648107PRTArtificial
SequenceSynthetic 648Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe
Ala Thr Tyr Tyr Cys Leu Gln Asp Phe Asn Tyr Pro Leu 85 90 95Thr Phe
Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105649357DNAArtificial
SequenceSynthetic 649caggtgcagc tggtggagtc tgggggaggc gtggtccagc
ctgggaggtc cctgagactc 60tcctgtgtag cctctggatt caccttcagt agatatggca
tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg gctgatagtt
atatcatatg atggaattaa taaatactat 180gcagactccg tgaagggccg
attcaccatc tccagagaca attccaagaa cacggtgtat 240ctgcaaatga
acagcctgag agctgaggac acgggagtgt attactgtgc gaaaggggac
300ttttggagtg gttactttga ctactggggc cagggaaccc tggtcactgt ctcctca
357650119PRTArtificial SequenceSynthetic 650Gln Val Gln Leu Val Glu
Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Ile
Val Ile Ser Tyr Asp Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Gly Val Tyr Tyr
Cys 85 90 95Ala Lys Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly
Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser
11565124DNAArtificial SequenceSynthetic 651ggattcacct tcagtagata
tggc 246528PRTArtificial SequenceSynthetic 652Gly Phe Thr Phe Ser
Arg Tyr Gly 1 565324DNAArtificial SequenceSynthetic 653atatcatatg
atggaattaa taaa 246548PRTArtificial SequenceSynthetic 654Ile Ser
Tyr Asp Gly Ile Asn Lys 1 565536DNAArtificial SequenceSynthetic
655gcgaaagggg acttttggag tggttacttt gactac 3665612PRTArtificial
SequenceSynthetic 656Ala Lys Gly Asp Phe Trp Ser Gly Tyr Phe Asp
Tyr 1 5 10657336DNAArtificial SequenceSynthetic 657gacatcgtga
tgacccagac tccactctcc tcacctgtca cccttggaca gccggcctcc 60atctcctgca
ggtctagtca aagcctcgtc cacagtgatg gaaacaccta cttgagttgg
120cttcaccaga ggccaggcca gcctccaaga ctcctaattt ataagatttc
taaccggttc 180tctggggtcc cagacagatt cagtggcagt ggggcaggga
cagatttcac actgcaaatc 240agcagggtgg aagctgagga tgtcgggatt
tattactgca tgcaaggtac acaatttccg 300actttcggcg gagggaccaa
ggtggagatc aaacga 336658112PRTArtificial SequenceSynthetic 658Asp
Ile Val Met Thr Gln Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10
15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp Leu His Gln Arg Pro Gly Gln
Pro 35 40 45 Pro Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser
Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe
Thr Leu Gln Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Ile
Tyr Tyr Cys Met Gln Gly 85 90 95Thr Gln Phe Pro Thr Phe Gly Gly Gly
Thr Lys Val Glu Ile Lys Arg 100 105 11065933DNAArtificial
SequenceSynthetic 659caaagcctcg tccacagtga tggaaacacc tac
3366011PRTArtificial SequenceSynthetic 660Gln Ser Leu Val His Ser
Asp Gly Asn Thr Tyr 1 5 106619DNAArtificial SequenceSynthetic
661aagatttct 96623PRTArtificial SequenceSynthetic 662Lys Ile Ser
166324DNAArtificial SequenceSynthetic 663atgcaaggta cacaatttcc gact
246648PRTArtificial SequenceSynthetic 664Met Gln Gly Thr Gln Phe
Pro Thr 1 5665357DNAArtificial SequenceSynthetic 665caggtgcagc
tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgtag
cctctggatt caccttcagt agatatggca tgcactgggt ccgccaggct
120ccaggcaagg ggctggagtg gctgatagtt atatcatatg atggaattaa
taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca
attccaagaa cacggtgtat 240ctgcaaatga acagcctgag agctgaggac
acgggagtgt attactgtgc gaaaggggac 300ttttggagtg gttactttga
ctactggggc cagggaaccc tggtcaccgt ctcctca 357666119PRTArtificial
SequenceSynthetic 666Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Val Ala Ser
Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Ile Val Ile Ser Tyr Asp
Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Gly Val Tyr Tyr Cys 85 90 95Ala Lys
Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 115667333DNAArtificial
SequenceSynthetic 667gatattgtga tgacccagac tccactctcc tcacctgtca
cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgtc cacagtgatg
gaaacaccta cttgagttgg 120cttcaccaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgcaaatc 240agcagggtgg
aagctgagga tgtcgggatt tattactgca tgcaaggtac acaatttccg
300actttcggcg gagggaccaa ggtggagatc aaa 333668111PRTArtificial
SequenceSynthetic 668Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp
Leu His Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr Leu Gln Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln Gly 85 90 95Thr Gln
Phe Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105
110669357DNAArtificial SequenceSynthetic 669caggtgcagc tggtggagtc
tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt
caccttcagt agatatggca tgcactgggt ccgccaggct 120ccaggcaagg
ggctggagtg ggtggcagtt atatcatatg atggaattaa taaatactat
180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa
cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt
attactgtgc gaaaggggac 300ttttggagtg gttactttga ctactggggc
cagggaaccc tggtcaccgt ctcctca 357670119PRTArtificial
SequenceSynthetic 670Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp
Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys
Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 115671334DNAArtificial
SequenceSynthetic 671gatattgtga tgacccagac tccactctcc tcacctgtca
cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgtc cacagtgatg
gaaacaccta cttgagttgg 120cttcagcaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgaaaatc 240agcagggtgg
aagctgagga tgtcggggtt tattactgca tgcaaggtac acaatttccg
300actttcggcg gagggaccaa ggtggagatc aaac 334672111PRTArtificial
SequenceSynthetic 672Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp
Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Thr Gln
Phe Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105
110673357DNAArtificial SequenceSynthetic 673caggtgcagc tggtgcagtc
tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgtag cctctggatt
caccttcagt agatatggca tgcactgggt ccgccaggct 120ccaggcaagg
ggctggagtg ggtggtagtt atatcatatg atggaattaa taaatactat
180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa
cacggtgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt
atcactgtgc gaaaggggac 300ttttggagtg gttactttga ctactggggc
cagggaaccc tggtcaccgt ctcctca 357674119PRTArtificial
SequenceSynthetic 674Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Val Ala Ser
Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Val Val Ile Ser Tyr Asp
Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys 85 90 95Ala Lys
Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 11567524DNAArtificial
SequenceSynthetic 675ggattcacct tcagtagata tggc 246768PRTArtificial
SequenceSynthetic 676Gly Phe Thr Phe Ser Arg Tyr Gly 1
567724DNAArtificial SequenceSynthetic 677atatcatatg atggaattaa taaa
246788PRTArtificial SequenceSynthetic 678Ile Ser Tyr Asp Gly Ile
Asn Lys 1 567936DNAArtificial SequenceSynthetic 679gcgaaagggg
acttttggag tggttacttt gactac 3668012PRTArtificial SequenceSynthetic
680Ala Lys Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr 1 5
10681336DNAArtificial SequenceSynthetic 681gacatcgtga tgacccagac
tccactctcc tcacctgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca
aagcctcgta cacagtgatg gaaacaccta cttgagttgg 120cttcaccaga
ggccaggcca gcctccaaga ctcctaattt ataagatttc taaccggttc
180tctggggtcc cagacagatt cagtggcagt ggggcaggga cagatttcac
actgcaaatc 240agcagggtgg aagctgagga tgtcgggatt tattactgca
tgcaagcaac acaatttccg 300actttcggcg gagggaccaa ggtggaaatc aaacga
336682112PRTArtificial SequenceSynthetic 682Asp Ile Val Met Thr Gln
Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser
Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn
Thr Tyr Leu Ser Trp Leu His Gln Arg Pro Gly Gln Pro 35 40 45 Pro
Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55
60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Gln Ile65
70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln
Ala 85 90 95Thr Gln Phe Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
Lys Arg 100 105 11068333DNAArtificial SequenceSynthetic
683caaagcctcg tacacagtga tggaaacacc tac 3368411PRTArtificial
SequenceSynthetic 684Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr 1
5 106859DNAArtificial SequenceSynthetic 685aagatttct
96863PRTArtificial SequenceSynthetic 686Lys Ile Ser
168724DNAArtificial SequenceSynthetic 687atgcaagcaa cacaatttcc gact
246888PRTArtificial SequenceSynthetic 688Met Gln Ala Thr Gln Phe
Pro Thr 1 5689357DNAArtificial SequenceSynthetic 689caggtgcagc
tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgtag
cctctggatt caccttcagt agatatggca tgcactgggt ccgccaggct
120ccaggcaagg ggctggagtg ggtggtagtt atatcatatg atggaattaa
taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca
attccaagaa cacggtgtat 240ctgcaaatga acagcctgag agctgaggac
acggctgtgt atcactgtgc gaaaggggac 300ttttggagtg gttactttga
ctactggggc cagggaaccc tggtcaccgt ctcctca 357690119PRTArtificial
SequenceSynthetic 690Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Val Ala Ser
Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Val Val Ile Ser Tyr Asp
Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys 85 90 95Ala Lys
Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 115691333DNAArtificial
SequenceSynthetic 691gatattgtga tgacccagac tccactctcc tcacctgtca
cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgta cacagtgatg
gaaacaccta cttgagttgg 120cttcaccaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgcaaatc 240agcagggtgg
aagctgagga tgtcgggatt tattactgca tgcaagcaac acaatttccg
300actttcggcg gagggaccaa ggtggagatc aaa 333692111PRTArtificial
SequenceSynthetic 692Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp
Leu His Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr Leu Gln Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln
Phe Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105
110693357DNAArtificial SequenceSynthetic 693caggtgcagc tggtggagtc
tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt
caccttcagt agatatggca tgcactgggt ccgccaggct 120ccaggcaagg
ggctggagtg ggtggcagtt atatcatatg atggaattaa taaatactat
180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa
cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt
attactgtgc gaaaggggac 300ttttggagtg gttactttga ctactggggc
cagggaaccc tggtcaccgt ctcctca 357694119PRTArtificial
SequenceSynthetic 694Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp
Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
Tyr Tyr Cys 85 90 95Ala Lys Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr
Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser
115695334DNAArtificial SequenceSynthetic 695gatattgtga tgacccagac
tccactctcc tcacctgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca
aagcctcgta cacagtgatg gaaacaccta cttgagttgg 120cttcagcaga
ggccaggcca gcctccaaga ctcctaattt ataagatttc taaccggttc
180tctggggtcc cagacagatt cagtggcagt ggggcaggga cagatttcac
actgaaaatc 240agcagggtgg aagctgagga tgtcggggtt tattactgca
tgcaagcaac acaatttccg 300actttcggcg gagggaccaa ggtggagatc aaac
334696111PRTArtificial SequenceSynthetic 696Asp Ile Val Met Thr Gln
Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser
Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn
Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro
Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55
60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65
70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln
Ala 85 90 95Thr Gln Phe Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
Lys 100 105 110697357DNAArtificial SequenceSynthetic 697caggtgcagc
tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgtag
cctctggatt caccttcagt agatatggca tacactgggt ccgccaggct
120ccaggcaagg ggctggagtg ggtgatagtt atatcatatg atggaattaa
taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca
attccaagaa cacggtatat 240ctgcaaatga acagcctgag agccgaggac
acggctgtgt attactgtgc gaaaggggac 300ttttggagtg gttactttga
ctattggggc cagggaaccc tggtcaccgt ctcctca 357698119PRTArtificial
SequenceSynthetic 698Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Val Ala Ser
Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Ile His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ile Val Ile Ser Tyr Asp
Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys
Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 11569924DNAArtificial
SequenceSynthetic 699ggattcacct tcagtagata tggc 247008PRTArtificial
SequenceSynthetic 700Gly Phe Thr Phe Ser Arg Tyr Gly 1
570124DNAArtificial SequenceSynthetic 701atatcatatg atggaattaa taaa
247028PRTArtificial SequenceSynthetic 702Ile Ser Tyr Asp Gly Ile
Asn Lys 1 570336DNAArtificial SequenceSynthetic 703gcgaaagggg
acttttggag tggttacttt gactat 3670412PRTArtificial SequenceSynthetic
704Ala Lys Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr 1 5
10705336DNAArtificial SequenceSynthetic 705gaaattgtgc tgactcagac
tccactctct tcacctgtca cccttggaca gccggcctcc 60atctcctgta ggtctaatca
aagcctcgta cacagtgatg gaaacaccta cttgagttgg 120cttcaccaga
ggccaggcca gcctccaaga ctcctaattt ataagatttc taaccggttc
180tctggggtcc cagacagatt cagtggcagt ggggcaggga cagatttcac
actgcaaatc 240agcagggtgg aagctgagga tgtcggtatt tattactgca
tgcaagctac acaatttccg 300actttcggcg gagggaccaa ggtggaaatc aaacga
336706112PRTArtificial SequenceSynthetic 706Glu Ile Val Leu Thr Gln
Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser
Ile Ser Cys Arg Ser Asn Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn
Thr Tyr Leu Ser Trp Leu His Gln Arg Pro Gly Gln Pro 35 40 45 Pro
Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55
60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Gln Ile65
70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln
Ala 85 90 95Thr Gln Phe Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
Lys Arg 100 105 11070733DNAArtificial SequenceSynthetic
707caaagcctcg tacacagtga tggaaacacc tac 3370811PRTArtificial
SequenceSynthetic 708Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr 1
5 107099DNAArtificial SequenceSynthetic 709aagatttct
97103PRTArtificial SequenceSynthetic 710Lys Ile Ser
171124DNAArtificial SequenceSynthetic 711atgcaagcta cacaatttcc gact
247128PRTArtificial SequenceSynthetic 712Met Gln Ala Thr Gln Phe
Pro Thr 1 5713357DNAArtificial SequenceSynthetic 713caggtgcagc
tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgtag
cctctggatt caccttcagt agatatggca tacactgggt ccgccaggct
120ccaggcaagg ggctggagtg ggtgatagtt atatcatatg atggaattaa
taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca
attccaagaa cacggtatat 240ctgcaaatga acagcctgag agccgaggac
acggctgtgt attactgtgc gaaaggggac 300ttttggagtg gttactttga
ctattggggc cagggaaccc tggtcaccgt ctcctca 357714119PRTArtificial
SequenceSynthetic 714Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Val Ala Ser
Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Ile His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ile Val Ile Ser Tyr Asp
Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys
Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 115715333DNAArtificial
SequenceSynthetic 715gatattgtga tgacccagac tccactctct tcacctgtca
cccttggaca gccggcctcc 60atctcctgta ggtctaatca aagcctcgta cacagtgatg
gaaacaccta cttgagttgg 120cttcaccaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgcaaatc 240agcagggtgg
aagctgagga tgtcggtatt tattactgca tgcaagctac acaatttccg
300actttcggcg gagggaccaa ggtggagatc aaa 333716111PRTArtificial
SequenceSynthetic 716Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Asn Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp
Leu His Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr Leu Gln Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln
Phe Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105
110717357DNAArtificial SequenceSynthetic 717caggtgcagc tggtggagtc
tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt
caccttcagt agatatggca tgcactgggt ccgccaggct 120ccaggcaagg
ggctggagtg ggtggcagtt atatcatatg atggaattaa taaatactat
180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa
cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt
attactgtgc gaaaggggac 300ttttggagtg gttactttga ctattggggc
cagggaaccc tggtcaccgt ctcctca 357718119PRTArtificial
SequenceSynthetic 718Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp
Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys
Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 115719334DNAArtificial
SequenceSynthetic 719gatattgtga tgacccagac tccactctcc tcacctgtca
cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgta cacagtgatg
gaaacaccta cttgagttgg 120cttcagcaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgaaaatc 240agcagggtgg
aagctgagga tgtcggggtt tattactgca tgcaagctac acaatttccg
300actttcggcg gagggaccaa ggtggagatc aaac 334720111PRTArtificial
SequenceSynthetic 720Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp
Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln
Phe Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105
110721357DNAArtificial SequenceSynthetic 721caggtgcagc tggtggagtc
tgggggaggc gtggtccagc ctgggatgtc cctgagactc 60tcctgtacag cgtccggatt
tacgttcagg agatatggca tgcactgggt ccgccaggct 120ccaggcaagg
ggctggagtg ggtggcagtt atttggtatg atggaagtaa taaatattat
180gcagactccg tgaagggacg attcaccata accagagaca attccaagaa
cacgttgtat 240ctgcaaatga acagcctgag agccgaggac acggctatat
atttttgtgc gagcgaaata 300acaattgggg actggttcga cccccggggc
cagggaaccc tggtcaccgt ctcctca 357722119PRTArtificial
SequenceSynthetic 722Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
Val Gln Pro Gly Met 1 5 10 15Ser Leu Arg Leu Ser Cys Thr Ala Ser
Gly Phe Thr Phe Arg Arg Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp
Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Thr Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Phe Cys 85 90 95Ala Ser
Glu Ile Thr Ile Gly Asp Trp Phe Asp Pro Arg Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 11572324DNAArtificial
SequenceSynthetic 723ggatttacgt tcaggagata tggc 247248PRTArtificial
SequenceSynthetic 724Gly Phe Thr Phe Arg Arg Tyr Gly 1
572524DNAArtificial SequenceSynthetic 725atttggtatg atggaagtaa taaa
247268PRTArtificial SequenceSynthetic 726Ile Trp Tyr Asp Gly Ser
Asn Lys 1 572736DNAArtificial SequenceSynthetic 727gcgagcgaaa
taacaattgg ggactggttc gacccc 3672812PRTArtificial SequenceSynthetic
728Ala Ser Glu Ile Thr Ile Gly Asp Trp Phe Asp Pro 1 5
10729324DNAArtificial SequenceSynthetic 729gccatccaga tgacccagtc
tccatcctcc ctgtctgcat ctgttggaga cagagtcacc 60atcacttgtc gggcaagtca
gggcattaga aatgatttag gctggtttca acagaaacca 120gggaaagtcc
ctaaactcct gatctatgct gcatccactt tacacagtgg ggtcccatca
180aggttcagcg gcagtggatt tggcacagat ttcactctca ccatcagcag
cctgcagcct 240gaagattttg caacttatta ctgtctacag gatttcaatt
accctctcac tttcggcgga 300gggaccaagg tggagatcaa acga
324730108PRTArtificial SequenceSynthetic 730Ala Ile Gln Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp
Phe Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Thr Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Phe Asn Tyr Pro
Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100
10573118DNAArtificial SequenceSynthetic 731cagggcatta gaaatgat
187326PRTArtificial SequenceSynthetic 732Gln Gly Ile Arg Asn Asp 1
57339DNAArtificial SequenceSynthetic 733gctgcatcc
97343PRTArtificial SequenceSynthetic 734Ala Ala Ser
173527DNAArtificial SequenceSynthetic 735ctacaggatt tcaattaccc
tctcact 277369PRTArtificial SequenceSynthetic 736Leu Gln Asp Phe
Asn Tyr Pro Leu Thr 1 5737357DNAArtificial SequenceSynthetic
737caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggatgtc
cctgagactc 60tcctgtacag cgtccggatt tacgttcagg agatatggca tgcactgggt
ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atttggtatg
atggaagtaa taaatattat 180gcagactccg tgaagggacg attcaccata
accagagaca attccaagaa cacgttgtat 240ctgcaaatga acagcctgag
agccgaggac acggctatat atttttgtgc gagcgaaata 300acaattgggg
actggttcga cccccggggc cagggaaccc tggtcaccgt ctcctca
357738119PRTArtificial SequenceSynthetic 738Gln Val Gln Leu Val Glu
Ser Gly Gly Gly Val Val Gln Pro Gly Met 1 5 10 15Ser Leu Arg Leu
Ser Cys Thr Ala Ser Gly Phe Thr Phe Arg Arg Tyr 20 25 30Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Thr Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Phe
Cys 85 90 95Ala Ser Glu Ile Thr Ile Gly Asp Trp Phe Asp Pro Arg Gly
Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser
115739321DNAArtificial SequenceSynthetic 739gccatccaga tgacccagtc
tccatcctcc ctgtctgcat ctgttggaga cagagtcacc 60atcacttgtc gggcaagtca
gggcattaga aatgatttag gctggtttca acagaaacca 120gggaaagtcc
ctaaactcct gatctatgct gcatccactt tacacagtgg ggtcccatca
180aggttcagcg gcagtggatt tggcacagat ttcactctca ccatcagcag
cctgcagcct 240gaagattttg caacttatta ctgtctacag gatttcaatt
accctctcac tttcggcgga 300gggaccaagg tggagatcaa a
321740107PRTArtificial SequenceSynthetic 740Ala Ile Gln Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp
Phe Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Thr Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Phe Asn Tyr Pro
Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100
105741357DNAArtificial SequenceSynthetic 741caggtgcagc tggtggagtc
tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt
tacgttcagg agatatggca tgcactgggt ccgccaggct 120ccaggcaagg
ggctggagtg ggtggcagtt atttggtatg atggaagtaa taaatactat
180gcagactccg tgaagggccg attcaccatc tccagagaca actccaagaa
cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt
attactgtgc gagcgaaata 300acaattgggg actggttcga cccccggggc
cagggaaccc tggtcaccgt ctcctca 357742119PRTArtificial
SequenceSynthetic 742Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Arg Arg Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp
Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Ser
Glu Ile Thr Ile Gly Asp Trp Phe Asp Pro Arg Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 115743322DNAArtificial
SequenceSynthetic 743gccatccaga tgacccagtc tccatcctcc ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaga aatgatttag
gctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct
gcatccagtt tacaaagtgg ggtcccatca 180aggttcagcg gcagtggatc
tggcacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg
caacttatta ctgtctacag gatttcaatt accctctcac tttcggcgga
300gggaccaagg tggagatcaa ac 322744107PRTArtificial
SequenceSynthetic 744Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe
Ala Thr Tyr Tyr Cys Leu Gln Asp Phe Asn Tyr Pro Leu 85 90 95Thr Phe
Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105745357DNAArtificial
SequenceSynthetic 745caggtgcagc tggtgcagtc tgggggaggc gtggtccagc
ctgggaggtc cctgagactc 60tcctgtgtag cctctggatt caccttcagt agatatggca
tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggtagtt
atatcatatg atggaattaa taaatactat 180gcagactccg tgaagggccg
attcaccatc tccagagaca attccaagaa cacggtgtat 240ctgcaaatga
acagcctgag agctgaggac acggctgtgt attactgtgc gaaaggggac
300ttttggagtg gttactttga ctactggggc cagggaaccc tggtcaccgt ctcctca
357746119PRTArtificial SequenceSynthetic 746Gln Val Gln Leu Val Gln
Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Val
Val Ile Ser Tyr Asp Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95Ala Lys Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly
Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser
11574724DNAArtificial SequenceSynthetic 747ggattcacct tcagtagata
tggc 247488PRTArtificial SequenceSynthetic 748Gly Phe Thr Phe Ser
Arg Tyr Gly 1 574924DNAArtificial SequenceSynthetic 749atatcatatg
atggaattaa taaa 247508PRTArtificial SequenceSynthetic 750Ile Ser
Tyr Asp Gly Ile Asn Lys 1 575136DNAArtificial SequenceSynthetic
751gcgaaagggg acttttggag tggttacttt gactac 3675212PRTArtificial
SequenceSynthetic 752Ala Lys Gly Asp Phe Trp Ser Gly Tyr Phe Asp
Tyr 1 5 10753336DNAArtificial SequenceSynthetic 753gaaattgtgc
tgactcagac tccactctcc tcacctgtca cccttggaca gccggcctcc 60atctcctgca
ggtctagtca aagcctcgta cacagtgatg gaaacaccta cttgagttgg
120cttcaccaga ggccaggcca gcctccaaga ctcctaattt ataagatttc
taaccggttc 180tctggggtcc cagacagatt cagtggcagt ggggcaggga
cagatttcac actgcaaatc 240agcagggtgg aagctgagga tgtcgggatt
tattactgca tgcaagctac acaatttccg 300actttcggcg gagggaccaa
ggtggagatc aaacga 336754112PRTArtificial SequenceSynthetic 754Glu
Ile Val Leu Thr Gln Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10
15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp Leu His Gln Arg Pro Gly Gln
Pro 35 40 45 Pro Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser
Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe
Thr Leu Gln Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Ile
Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln Phe Pro Thr Phe Gly Gly Gly
Thr Lys Val Glu Ile Lys Arg 100 105 11075533DNAArtificial
SequenceSynthetic 755caaagcctcg tacacagtga tggaaacacc tac
3375611PRTArtificial SequenceSynthetic 756Gln Ser Leu Val His Ser
Asp Gly Asn Thr Tyr 1 5 107579DNAArtificial SequenceSynthetic
757aagatttct 97583PRTArtificial SequenceSynthetic 758Lys Ile Ser
175924DNAArtificial SequenceSynthetic 759atgcaagcta cacaatttcc gact
247608PRTArtificial SequenceSynthetic 760Met Gln Ala Thr Gln Phe
Pro Thr 1 5761357DNAArtificial SequenceSynthetic 761caggtgcagc
tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgtag
cctctggatt caccttcagt agatatggca tgcactgggt ccgccaggct
120ccaggcaagg ggctggagtg ggtggtagtt atatcatatg atggaattaa
taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca
attccaagaa cacggtgtat 240ctgcaaatga acagcctgag agctgaggac
acggctgtgt attactgtgc gaaaggggac 300ttttggagtg gttactttga
ctactggggc cagggaaccc tggtcaccgt ctcctca 357762119PRTArtificial
SequenceSynthetic 762Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Val Ala Ser
Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Val Val Ile Ser Tyr Asp
Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys
Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 115763333DNAArtificial
SequenceSynthetic 763gatattgtga tgacccagac tccactctcc tcacctgtca
cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgta cacagtgatg
gaaacaccta cttgagttgg 120cttcaccaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgcaaatc 240agcagggtgg
aagctgagga tgtcgggatt tattactgca tgcaagctac acaatttccg
300actttcggcg gagggaccaa ggtggagatc aaa 333764111PRTArtificial
SequenceSynthetic 764Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp
Leu His Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr Leu Gln Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln
Phe Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105
110765357DNAArtificial SequenceSynthetic 765caggtgcagc tggtggagtc
tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt
caccttcagt agatatggca tgcactgggt ccgccaggct 120ccaggcaagg
ggctggagtg ggtggcagtt atatcatatg atggaattaa taaatactat
180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa
cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt
attactgtgc gaaaggggac 300ttttggagtg gttactttga ctactggggc
cagggaaccc tggtcaccgt ctcctca 357766119PRTArtificial
SequenceSynthetic 766Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp
Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys
Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 115767334DNAArtificial
SequenceSynthetic 767gatattgtga tgacccagac tccactctcc tcacctgtca
cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgta cacagtgatg
gaaacaccta cttgagttgg 120cttcagcaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgaaaatc 240agcagggtgg
aagctgagga tgtcggggtt tattactgca tgcaagctac acaatttccg
300actttcggcg gagggaccaa ggtggagatc aaac 334768111PRTArtificial
SequenceSynthetic 768Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp
Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr
Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly
Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val
Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Thr Gln
Phe Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105
110769357DNAArtificial SequenceSynthetic 769gaggtgcagc tggtgcagtc
tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgtag cctctggatt
caccttcagt agatatggca tgcactgggt ccgccaggct 120ccaggcaagg
ggctggagtg gctgatagtt atatcatatg atggaattaa taaatactat
180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa
cacggtgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt
attactgtgc gaaaggggac 300ttttggagtg gatactttga ctactggggc
cagggaaccc tggtcaccgt ctcctca 357770119PRTArtificial
SequenceSynthetic 770Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Val Ala Ser
Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Ile Val Ile Ser Tyr Asp
Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys
Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 11577124DNAArtificial
SequenceSynthetic 771ggattcacct tcagtagata tggc 247728PRTArtificial
SequenceSynthetic 772Gly Phe Thr Phe Ser Arg Tyr Gly 1
577324DNAArtificial SequenceSynthetic 773atatcatatg atggaattaa taaa
247748PRTArtificial SequenceSynthetic 774Ile Ser Tyr Asp Gly Ile
Asn Lys 1 577536DNAArtificial SequenceSynthetic 775gcgaaagggg
acttttggag tggatacttt gactac 3677612PRTArtificial SequenceSynthetic
776Ala Lys Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr 1 5
10777336DNAArtificial SequenceSynthetic 777gacatcgtga tgacccagac
tccactctcc tcacctgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca
aagcctcgta cacagtgatg gaaacaccta cttgagttgg 120cttcaccaga
ggccaggcca gcctccaaga ctcctaattt ataagatttc taaccggttc
180tctggggtcc cagacagatt cagtggcagt ggggcaggga cagatttcac
actgcaaatc 240agcagggtgg aagctgagga tgtcgggatt tattactgca
tgcaaggtac acaatttccg 300actttcggcg gagggaccaa ggtggagatc aaacga
336778112PRTArtificial SequenceSynthetic 778Asp Ile Val Met Thr Gln
Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser
Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn
Thr Tyr Leu Ser Trp Leu His Gln Arg Pro Gly Gln Pro 35 40 45 Pro
Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55
60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Gln Ile65
70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln
Gly 85 90 95Thr Gln Phe Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
Lys Arg 100 105 11077933DNAArtificial SequenceSynthetic
779caaagcctcg tacacagtga tggaaacacc tac 3378011PRTArtificial
SequenceSynthetic 780Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr 1
5 107819DNAArtificial SequenceSynthetic 781aagatttct
97823PRTArtificial SequenceSynthetic 782Lys Ile Ser
178324DNAArtificial SequenceSynthetic 783atgcaaggta cacaatttcc gact
247848PRTArtificial SequenceSynthetic 784Met Gln Gly Thr Gln Phe
Pro Thr 1 5785357DNAArtificial SequenceSynthetic 785caggtgcagc
tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgtag
cctctggatt caccttcagt agatatggca tgcactgggt ccgccaggct
120ccaggcaagg ggctggagtg gctgatagtt atatcatatg atggaattaa
taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca
attccaagaa cacggtgtat 240ctgcaaatga acagcctgag agctgaggac
acggctgtgt attactgtgc gaaaggggac 300ttttggagtg gatactttga
ctactggggc cagggaaccc tggtcaccgt ctcctca 357786119PRTArtificial
SequenceSynthetic 786Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Val Ala Ser
Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Ile Val Ile Ser Tyr Asp
Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys
Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 115787333DNAArtificial
SequenceSynthetic 787gatattgtga tgacccagac tccactctcc tcacctgtca
cccttggaca gccggcctcc 60atctcctgca ggtctagtca aagcctcgta cacagtgatg
gaaacaccta cttgagttgg 120cttcaccaga ggccaggcca gcctccaaga
ctcctaattt ataagatttc taaccggttc 180tctggggtcc cagacagatt
cagtggcagt ggggcaggga cagatttcac actgcaaatc 240agcagggtgg
aagctgagga tgtcgggatt tattactgca tgcaaggtac acaatttccg
300actttcggcg gagggaccaa ggtggagatc aaa 333788111PRTArtificial
SequenceSynthetic 788Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser
Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser
Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn Thr Tyr Leu Ser Trp
Leu His Gln Arg Pro Gly Gln Pro 35
40 45 Pro Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val
Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu
Gln Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr
Cys Met Gln Gly 85 90 95Thr Gln Phe Pro Thr Phe Gly Gly Gly Thr Lys
Val Glu Ile Lys 100 105 110789357DNAArtificial SequenceSynthetic
789caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc
cctgagactc 60tcctgtgcag cctctggatt caccttcagt agatatggca tgcactgggt
ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg
atggaattaa taaatactat 180gcagactccg tgaagggccg attcaccatc
tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag
agctgaggac acggctgtgt attactgtgc gaaaggggac 300ttttggagtg
gatactttga ctactggggc cagggaaccc tggtcaccgt ctcctca
357790119PRTArtificial SequenceSynthetic 790Gln Val Gln Leu Val Glu
Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Val Ile Ser Tyr Asp Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95Ala Lys Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly
Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser
115791334DNAArtificial SequenceSynthetic 791gatattgtga tgacccagac
tccactctcc tcacctgtca cccttggaca gccggcctcc 60atctcctgca ggtctagtca
aagcctcgta cacagtgatg gaaacaccta cttgagttgg 120cttcagcaga
ggccaggcca gcctccaaga ctcctaattt ataagatttc taaccggttc
180tctggggtcc cagacagatt cagtggcagt ggggcaggga cagatttcac
actgaaaatc 240agcagggtgg aagctgagga tgtcggggtt tattactgca
tgcaaggtac acaatttccg 300actttcggcg gagggaccaa ggtggagatc aaac
334792111PRTArtificial SequenceSynthetic 792Asp Ile Val Met Thr Gln
Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 1 5 10 15Gln Pro Ala Ser
Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30Asp Gly Asn
Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro
Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val Pro 50 55
60Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile65
70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln
Gly 85 90 95Thr Gln Phe Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
Lys 100 105 110793357DNAArtificial SequenceSynthetic 793caggtgcagc
tgcaggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgtag
cctctggatt caccttcagt agatatggca tgcactgggt ccgccaggct
120ccaggcaagg ggctggagtg ggtggtagtt atatcatatg atggaattaa
taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca
attccaagaa cacggtgtat 240ctgcaaatga acagcctgag agctgaggac
acggctgtgt attactgtgc gaaaggggac 300ttttggagtg gttactttga
ctactggggc cagggaaccc tggtcaccgt ctcctca 357794119PRTArtificial
SequenceSynthetic 794Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Val Ala Ser
Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Val Val Ile Ser Tyr Asp
Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys
Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 11579524DNAArtificial
SequenceSynthetic 795ggattcacct tcagtagata tggc 247968PRTArtificial
SequenceSynthetic 796Gly Phe Thr Phe Ser Arg Tyr Gly 1
579724DNAArtificial SequenceSynthetic 797atatcatatg atggaattaa taaa
247988PRTArtificial SequenceSynthetic 798Ile Ser Tyr Asp Gly Ile
Asn Lys 1 579936DNAArtificial SequenceSynthetic 799gcgaaagggg
acttttggag tggttacttt gactac 3680012PRTArtificial SequenceSynthetic
800Ala Lys Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr 1 5
10801321DNAArtificial SequenceSynthetic 801gacatccaga tgacccagtc
tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca
gggcattaga aatgatttag gctggtatca gcagaaacca 120gggaaagccc
ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca
180aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag
cctgcagcct 240gaagattttg caacttatta ctgtctacag cataatagtt
accctccgac gttcggccaa 300gggaccaagg tggagatcaa a
321802107PRTArtificial SequenceSynthetic 802Asp Ile Gln Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro
Pro 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100
10580318DNAArtificial SequenceSynthetic 803cagggcatta gaaatgat
188046PRTArtificial SequenceSynthetic 804Gln Gly Ile Arg Asn Asp 1
58059DNAArtificial SequenceSynthetic 805gctgcatcc
98063PRTArtificial SequenceSynthetic 806Ala Ala Ser
180727DNAArtificial SequenceSynthetic 807ctacagcata atagttaccc
tccgacg 278089PRTArtificial SequenceSynthetic 808Leu Gln His Asn
Ser Tyr Pro Pro Thr 1 5809357DNAArtificial SequenceSynthetic
809caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc
cctgagactc 60tcctgtgtag cctctggatt caccttcagt agatatggca tgcactgggt
ccgccaggct 120ccaggcaagg ggctggagtg ggtggtagtt atatcatatg
atggaattaa taaatactat 180gcagactccg tgaagggccg attcaccatc
tccagagaca attccaagaa cacggtgtat 240ctgcaaatga acagcctgag
agctgaggac acggctgtgt attactgtgc gaaaggggac 300ttttggagtg
gttactttga ctactggggc cagggaaccc tggtcaccgt ctcctca
357810119PRTArtificial SequenceSynthetic 810Gln Val Gln Leu Val Glu
Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Val
Val Ile Ser Tyr Asp Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95Ala Lys Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly
Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser
115811321DNAArtificial SequenceSynthetic 811gacatccaga tgacccagtc
tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca
gggcattaga aatgatttag gctggtatca gcagaaacca 120gggaaagccc
ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca
180aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag
cctgcagcct 240gaagattttg caacttatta ctgtctacag cataatagtt
accctccgac gttcggccaa 300gggaccaagg tggaaatcaa a
321812107PRTArtificial SequenceSynthetic 812Asp Ile Gln Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro
Pro 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100
105813357DNAArtificial SequenceSynthetic 813caggtgcagc tggtggagtc
tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt
caccttcagt agatatggca tgcactgggt ccgccaggct 120ccaggcaagg
ggctggagtg ggtggcagtt atatcatatg atggaattaa taaatactat
180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa
cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt
attactgtgc gaaaggggac 300ttttggagtg gttactttga ctactggggc
cagggaaccc tggtcaccgt ctcctca 357814119PRTArtificial
SequenceSynthetic 814Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp
Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys
Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 115815322DNAArtificial
SequenceSynthetic 815gacatccaga tgacccagtc tccatcctcc ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaga aatgatttag
gctggtatca gcagaaacca 120gggaaagccc ctaagcgcct gatctatgct
gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc
tgggacagaa ttcactctca caatcagcag cctgcagcct 240gaagattttg
caacttatta ctgtctacag cataatagtt accctccgac gttcggccaa
300gggaccaagg tggaaatcaa ac 322816107PRTArtificial
SequenceSynthetic 816Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
Ser Ala Ser Val Gly 1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln Gly Ile Arg Asn Asp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe
Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Pro 85 90 95Thr Phe
Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105817357DNAArtificial
SequenceSynthetic 817gaggtgcagc tggtggagtc tgggggaggc gtggtccagc
ctgggaggtc cctgagactc 60tcctgtgtag cctctggatt caccttcagt agatatggca
tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg gctgatagtt
atatcatatg atggaattaa taaatactat 180gcagactccg tgaagggccg
attcaccatc tccagagaca attccaagaa cacggtgtat 240ctgcaaatga
acagcctgag agttgaggac acgggagtgt attactgtgc gaaaggggac
300ttttggagtg gttactttga ctactggggc cagggaaccc tggtcaccgt ctcctca
357818119PRTArtificial SequenceSynthetic 818Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Ile
Val Ile Ser Tyr Asp Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Gly Val Tyr Tyr
Cys 85 90 95Ala Lys Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly
Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser
11581924DNAArtificial SequenceSynthetic 819ggattcacct tcagtagata
tggc 248208PRTArtificial SequenceSynthetic 820Gly Phe Thr Phe Ser
Arg Tyr Gly 1 582124DNAArtificial SequenceSynthetic 821atatcatatg
atggaattaa taaa 248228PRTArtificial SequenceSynthetic 822Ile Ser
Tyr Asp Gly Ile Asn Lys 1 582336DNAArtificial SequenceSynthetic
823gcgaaagggg acttttggag tggttacttt gactac 3682412PRTArtificial
SequenceSynthetic 824Ala Lys Gly Asp Phe Trp Ser Gly Tyr Phe Asp
Tyr 1 5 10825327DNAArtificial SequenceSynthetic 825gaaattgtgt
tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca
gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac
tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc
tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag
cagtatggta gctcaccgtg gacgttcggc 300caagggacca aggtggaaat caaacga
327826109PRTArtificial SequenceSynthetic 826Glu Ile Val Leu Thr Gln
Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15Glu Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55
60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65
70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser
Pro 85 90 95Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100
10582721DNAArtificial SequenceSynthetic 827cagagtgtta gcagcagcta c
218287PRTArtificial SequenceSynthetic 828Gln Ser Val Ser Ser Ser
Tyr 1 58299DNAArtificial SequenceSynthetic 829ggtgcatcc
98303PRTArtificial SequenceSynthetic 830Gly Ala Ser
183127DNAArtificial SequenceSynthetic 831cagcagtatg gtagctcacc
gtggacg 278329PRTArtificial SequenceSynthetic 832Gln Gln Tyr Gly
Ser Ser Pro Trp Thr 1 5833357DNAArtificial SequenceSynthetic
833caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc
cctgagactc 60tcctgtgtag cctctggatt caccttcagt agatatggca tgcactgggt
ccgccaggct 120ccaggcaagg ggctggagtg gctgatagtt atatcatatg
atggaattaa taaatactat 180gcagactccg tgaagggccg attcaccatc
tccagagaca attccaagaa cacggtgtat 240ctgcaaatga acagcctgag
agttgaggac acgggagtgt attactgtgc gaaaggggac 300ttttggagtg
gttactttga ctactggggc cagggaaccc tggtcaccgt ctcctca
357834119PRTArtificial SequenceSynthetic 834Gln Val Gln Leu Val Glu
Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu
Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Ile
Val Ile Ser Tyr Asp Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Gly Val Tyr Tyr
Cys 85 90 95Ala Lys Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly
Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser
115835324DNAArtificial SequenceSynthetic 835gaaattgtgt tgacgcagtc
tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca
gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg
ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca
180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag
cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta
gctcaccgtg gacgttcggc 300caagggacca aggtggaaat caaa
324836108PRTArtificial SequenceSynthetic 836Glu Ile Val Leu Thr Gln
Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15Glu Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55
60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65
70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser
Pro 85 90 95Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100
105837357DNAArtificial SequenceSynthetic 837caggtgcagc tggtggagtc
tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt
caccttcagt agatatggca tgcactgggt ccgccaggct 120ccaggcaagg
ggctggagtg ggtggcagtt atatcatatg atggaattaa taaatactat
180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa
cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt
attactgtgc gaaaggggac 300ttttggagtg gttactttga ctactggggc
cagggaaccc tggtcaccgt ctcctca 357838119PRTArtificial
SequenceSynthetic 838Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Arg Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp
Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys
Gly Asp Phe Trp Ser Gly Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105
110Thr Leu Val Thr Val Ser Ser 115839325DNAArtificial
SequenceSynthetic 839gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt
ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact
tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat
ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg
gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt
ttgcagtgta ttactgtcag cagtatggta gctcaccgtg gacgttcggc
300caagggacca aggtggaaat caaac 325840108PRTArtificial
SequenceSynthetic 840Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
Ser Leu Ser Pro Gly 1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala
Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys
Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser
Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly
Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp
Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95Trp Thr
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 1058418PRTArtificial
SequenceSynthetic 841Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1
58428PRTArtificial SequenceSynthetic 842Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa 1 584312PRTArtificial SequenceSynthetic 843Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 1084411PRTArtificial
SequenceSynthetic 844Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1
5 108453PRTArtificial SequenceSynthetic 845Xaa Xaa Xaa
18469PRTArtificial SequenceSynthetic 846Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa 1 5847330PRTArtificial SequenceSynthetic 847Ala Ser Thr Lys
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15Ser Thr
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40
45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
Val Asp Lys 85 90 95Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile
Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser
His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185
190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
Ser Arg Asp Glu225 230 235 240Leu Thr Lys Asn Gln Val Ser Leu Thr
Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu
Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310
315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325
330848327PRTArtificial SequenceSynthetic 848Ala Ser Thr Lys Gly Pro
Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15Ser Thr Ser Glu
Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55
60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr65
70 75 80Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
Lys 85 90 95Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro
Ala Pro 100 105 110Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
Pro Lys Pro Lys 115 120 125Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
Val Thr Cys Val Val Val 130 135 140Asp Val Ser Gln Glu Asp Pro Glu
Val Gln Phe Asn Trp Tyr Val Asp145 150 155 160Gly Val Glu Val His
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 165 170 175Asn Ser Thr
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190Trp
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200
205Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met
Thr Lys225 230 235 240Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
Phe Tyr Pro Ser Asp 245 250 255Ile Ala Val Glu Trp Glu Ser Asn Gly
Gln Pro Glu Asn Asn Tyr Lys 260 265 270Thr Thr Pro Pro Val Leu Asp
Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285Arg Leu Thr Val Asp
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300Cys Ser Val
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser305 310 315
320Leu Ser Leu Ser Leu Gly Lys 325849327PRTArtificial
SequenceSynthetic 849Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
Ala Pro Cys Ser Arg 1 5 10 15Ser Thr Ser Glu Ser Thr Ala Ala Leu
Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser
Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val
Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr65 70 75 80Tyr Thr Cys
Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Arg Val
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105
110Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
Val Val 130 135 140Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
Trp Tyr Val Asp145 150 155 160Gly Val Glu Val His Asn Ala Lys Thr
Lys Pro Arg Glu Glu Gln Phe 165 170 175Asn Ser Thr Tyr Arg Val Val
Ser Val Leu Thr Val Leu His Gln Asp 180 185 190Trp Leu Asn Gly Lys
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205Pro Ser Ser
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220Glu
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys225 230
235 240Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
Asp 245 250 255Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
Asn Tyr Lys 260 265 270Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
Phe Phe Leu Tyr Ser 275 280 285Arg Leu Thr Val Asp Lys Ser Arg Trp
Gln Glu Gly Asn Val Phe Ser 290 295 300Cys Ser Val Met His Glu Ala
Leu His Asn His Tyr Thr Gln Lys Ser305 310 315 320Leu Ser Leu Ser
Leu Gly Lys 3258501194DNAArtificial SequenceSynthetic 850atgcggagcc
ccagcgcggc gtggctgctg ggggccgcca tcctgctagc agcctctctc 60tcctgcagtg
gcaccatcca aggaaccaat agatcctcta aaggaagaag ccttattggt
120aaggttgatg gcacatccca cgtcactgga aaaggagtta cagttgaaac
agtcttttct 180gtggatgagt tttctgcatc tgtcctcact ggaaaactga
ccacggtctt ccttccaatt 240gtctacacaa ttgtgtttgt ggtgggtttg
ccaagtaacg gcatggccct gtgggtcttt 300cttttccgaa ctaagaagaa
gcaccctgct gtgatttaca tggccaatct ggccttggct 360gacctcctct
ctgtcatctg gttccccttg aagattgcct atcacataca tgccaacaac
420tggatttatg gggaagctct ttgtaatgtg cttattggct ttttctatgg
caacatgtac 480tgttccattc tcttcatgac ctgcctcagt gtgcagaggt
attgggtcat cgtgaacccc 540atggggcact ccaggaagaa ggcaaacatt
gccattggca tctccctggc aatatggctg 600ctgattctgc tggtcaccat
ccctttgtat gtcgtgaagc agaccatctt cattcctgcc 660ctgaacatca
cgacctgtca tgatgttttg cctgagcagc tcttggtggg agacatgttc
720aattacttcc tctctctggc cattggggtc tttctgttcc cagccttcct
cacagcctct 780gcctatgtgc tgatgatcag aatgctgcga tcttctgcca
tggatgaaaa ctcagagaag 840aaaaggaaga gggccatcaa actcattgtc
actgtcctgg ccatgtacct gatctgcttc 900actcctagta accttctgct
tgtggtgcat tattttctga ttaagagcca gggccagagc 960catgtctatg
ccctgtacat tgtagccctc tgcctctcta cccttaacag ctgcatcgac
1020ccctttgtct attactttgt ttcacatgat ttcagggatc atgcaaagaa
cgctctcctt 1080tgccgaagtg tccgcactgt aaagcagatg caagtatccc
tcacctcaaa gaaacactcc 1140aggaaatcca gctcttactc ttcaagttca
accactgtta agacctccta ttga 1194851397PRTArtificial
SequenceSynthetic 851Met Arg Ser Pro Ser Ala Ala Trp Leu Leu Gly
Ala Ala Ile Leu Leu 1 5 10 15Ala Ala Ser Leu Ser Cys Ser Gly Thr
Ile Gln Gly Thr Asn Arg Ser 20 25 30Ser Lys Gly Arg Ser Leu Ile Gly
Lys Val Asp Gly Thr Ser His Val 35 40 45 Thr Gly Lys Gly Val Thr
Val Glu Thr Val Phe Ser Val Asp Glu Phe 50 55 60Ser Ala Ser Val Leu
Thr Gly Lys Leu Thr Thr Val Phe Leu Pro Ile65 70 75 80Val Tyr Thr
Ile Val Phe Val Val Gly Leu Pro Ser Asn Gly Met Ala 85 90 95Leu Trp
Val Phe Leu Phe Arg Thr Lys Lys Lys His Pro Ala Val Ile 100 105
110Tyr Met Ala Asn Leu Ala Leu Ala Asp Leu Leu Ser Val Ile Trp Phe
115 120 125Pro Leu Lys Ile Ala Tyr His Ile His Ala Asn Asn Trp Ile
Tyr Gly 130 135 140Glu Ala Leu Cys Asn Val Leu Ile Gly Phe Phe Tyr
Gly Asn Met Tyr145 150 155 160Cys Ser Ile Leu Phe Met Thr Cys Leu
Ser Val Gln Arg Tyr Trp Val 165 170 175Ile Val Asn Pro Met Gly His
Ser Arg Lys Lys Ala Asn Ile Ala Ile 180 185 190Gly Ile Ser Leu Ala
Ile Trp Leu Leu Ile Leu Leu Val Thr Ile Pro 195 200 205Leu Tyr Val
Val Lys Gln Thr Ile Phe Ile Pro Ala Leu Asn Ile Thr 210 215 220Thr
Cys His Asp Val Leu Pro Glu Gln Leu Leu Val Gly Asp Met Phe225 230
235 240Asn Tyr Phe Leu Ser Leu Ala Ile Gly Val Phe Leu Phe Pro Ala
Phe 245 250 255Leu Thr Ala Ser Ala Tyr Val Leu Met Ile Arg Met Leu
Arg Ser Ser 260 265 270Ala Met Asp Glu Asn Ser Glu Lys Lys Arg Lys
Arg Ala Ile Lys Leu 275 280 285Ile Val Thr Val Leu Ala Met Tyr Leu
Ile Cys Phe Thr Pro Ser Asn 290 295 300Leu Leu Leu Val Val His Tyr
Phe Leu Ile Lys Ser Gln Gly Gln Ser305 310 315 320His Val Tyr Ala
Leu Tyr Ile Val Ala Leu Cys Leu Ser Thr Leu Asn 325 330 335Ser Cys
Ile Asp Pro Phe Val Tyr Tyr Phe Val Ser His Asp Phe Arg 340 345
350Asp His Ala Lys Asn Ala Leu Leu Cys Arg Ser Val Arg Thr Val Lys
355 360 365Gln Met Gln Val Ser Leu Thr Ser Lys Lys His Ser Arg Lys
Ser Ser 370 375 380Ser Tyr Ser Ser Ser Ser Thr Thr Val Lys Thr Ser
Tyr385 390 39585218PRTHuman 852Gly Thr Asn Arg Ser Ser Lys Gly Arg
Ser Leu Ile Gly Lys Val Asp 1 5 10 15Gly Thr85314PRTHuman 853Ser
Leu Ile Gly Lys Val Asp Gly Thr Ser His Val Thr Gly 1 5
108546PRTHuman 854Ser Leu Ile Gly Lys Val 1 5855276PRTArtificial
SequenceSynthetic 855Ser Leu Ile Gly Lys Val Asp Gly Thr Ser His
Val Thr Gly Lys Gly 1 5 10 15Val Thr Val Glu Thr Val Phe Ser Val
Asp Glu Phe Ser Ala Ser Val 20 25 30Leu Thr Gly Lys Leu Thr Thr Val
Phe Leu Pro Glu Pro Arg Gly Pro 35 40 45 Thr Ile Lys Pro Cys Pro
Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu 50 55 60Gly Gly Pro Ser Val
Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu65 70 75 80Met Ile Ser
Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser 85 90 95Glu Asp
Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu 100 105
110Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr
115 120 125Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp
Met Ser 130 135 140Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp
Leu Pro Ala Pro145 150 155 160Ile Glu Arg Thr Ile Ser Lys Pro Lys
Gly Ser Val Arg Ala Pro Gln 165 170 175Val Tyr Val Leu Pro Pro Pro
Glu Glu Glu Met Thr Lys Lys Gln Val 180 185 190Thr Leu Thr Cys Met
Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val 195 200 205Glu Trp Thr
Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu 210 215 220Pro
Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg225 230
235
240Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val
245 250 255Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe
Ser Arg 260 265 270Thr Pro Gly Lys 27585620PRTMouse 856Leu Ala Pro
Gly Arg Asn Asn Ser Lys Gly Arg Ser Leu Ile Gly Arg 1 5 10 15Leu
Glu Thr Gln 2085718PRTMonkey 857Gly Thr Asn Arg Ser Ser Lys Gly Arg
Ser Leu Ile Gly Arg Val Asp 1 5 10 15Gly Thr85816PRTRat 858Gly Pro
Asn Ser Lys Gly Arg Ser Leu Ile Gly Arg Leu Asp Thr Pro 1 5 10
1585918PRTRabbit 859Gly Thr Asn Lys Thr Ser Lys Gly Arg Ser Leu Ile
Gly Arg Asn Thr 1 5 10 15Gly Ser86018PRTDog 860Gly Thr Asn Arg Thr
Ser Lys Gly Arg Ser Leu Ile Gly Lys Thr Asp 1 5 10 15Ser
Ser86118PRTPig 861Gly Thr Ser Arg Pro Ser Lys Gly Arg Ser Leu Ile
Gly Lys Ala Asp 1 5 10 15Asn Thr86218PRTHuman 862Ala Thr Asn Ala
Thr Leu Asp Pro Arg Ser Phe Leu Leu Arg Asn Pro 1 5 10 15Asn
Asp86318PRTHuman 863Asp Thr Asn Asn Leu Ala Lys Pro Thr Leu Pro Ile
Lys Thr Phe Arg 1 5 10 15Gly Ala86419PRTHuman 864Glu Ser Gly Ser
Thr Gly Gly Gly Asp Asp Ser Thr Pro Ser Ile Leu 1 5 10 15Pro Ala
Pro8652772DNAMouse 865gtccgcccac gcgtccgggg aagggaccct gtgctcagag
tagggctccg agtttcgaac 60cactggtggc ggattgcccg cccgccccac gtccggggat
gcgaagtctc agcctggcgt 120ggctgctggg aggtatcacc cttctggcgg
cctcggtctc ctgcagccgg accgagaacc 180ttgcaccggg acgcaacaac
agtaaaggaa gaagtcttat tggcagattg gaaacccagc 240ctccaatcac
tgggaaaggg gttccggtag aaccaggctt ttccatcgat gagttctctg
300cgtccatcct caccgggaag ctgaccactg tctttcttcc ggtcgtctac
attattgtgt 360ttgtgattgg tttgcccagt aatggcatgg ccctctggat
cttccttttc cgaacgaaga 420agaaacaccc cgccgtgatt tacatggcca
acctggcctt ggctgacctc ctctctgtca 480tctggttccc cctggccatt
gcctaccacc tacatggcaa caactgggtc tatggggagg 540ccctgtgcaa
ggtgctcatt ggctttttct atggcaacat gtattgctcc atcctcttca
600tgacctgcct cagcgtgcag aggtactggg tgatcgtgaa ccccatgggg
caccccagga 660agaaggcaaa catcgccgtt ggcgtctcct tggcaatctg
gctcctgatt tttctggtca 720ccatcccttt gtatgtcatg aagcagacca
tctacattcc agccttgaac atcaccacct 780gccacgatgt gctgcctgag
gaggtattgg tgggggacat gttcaattac ttcctctcac 840tggccattgg
agtcttcctg ttcccggcca tccttactgc atctgcctac gtgctcatga
900tcaagacgct ccgctcttct gctatggatg aacactcaga gaagaaaagg
cagagggcta 960tccgactcat catcaccgtg ctggccatgt acttcatctg
ctttgctcct agcaaccttc 1020tgctcgtagt gcattatttc ctaatcaaaa
cccagaggca gagccacgtc tacgccctct 1080acctcgtcgc cctctgcctg
tcgactctca acagctgcat agaccccttt gtctattact 1140ttgtctcaaa
agatttcagg gatcacgcca ggaacgcgct cctctgccga agtgtccgca
1200ctgtgaatcg catgcaaatc tccctcagct ccaacaagtt ctccaggaag
tccggctcct 1260actcttcaag ctcaaccagt gttaaaacct cctactgagc
tgtacctgag gatgtcaagc 1320ctgcttgatg atgatgatga tgatgatgat
gatgtgtgtg tgtgtgtgtg tgtgtgtgtg 1380tgtgcacccg tgtgtgagag
cgtagtagga atgcaccaac atgcatgagg ctgtcatttc 1440ctatccaagc
tgctggtctc tgcaccaatc acaagcatgc agctctcccc aagatcgcca
1500gaagcctcct cctttgcatg agaacagtct tccactctga tgaaaagcat
cagtatcaga 1560aactgaaaca aactgagagg agcatgtttt gtggaagtga
agagaggatg gagggtcagt 1620gacttgcaaa aaaaacccaa ccaaacaaaa
acgacacctg gcaagaaggc taagactctc 1680tgaaatgctt ccttttccat
ctggagttcg tcacggcttt gttcaggacc tgaggccctg 1740gtagagcttc
agtccagttg attgacttta cagacttgag agaggaatga atgaggagtg
1800aatgcggctc ctggcggcat cctaaccggc taacagtggc cttgctggac
aataggattc 1860agatggctgg agttacattc tcacaccatt tcatcagaac
tattggggat cttgatcaat 1920gtgcaggtcc cttagcgtca gtaaccctgg
gagctcagac acgatggggg tgagggtggg 1980ggtgggggtg ggggtgaggc
tctacaaacc ttagtgatga ctgcagacac agaaccatgg 2040agctgagcct
gcttctgctt gccagggcac cactgtaatg ttggcaaaga aaaaccaaca
2100gcagtgtttt gagcctcttt ttttggtcag tttatgatga atttgcctat
tggtttattg 2160ggattttcag ttcctttatt actttgttgt aattttgtgt
gtttattagt caagaaaaag 2220aagatgaggc tcttaaaaat gtaaataaaa
tttttggttt tttggttttt taacttgggc 2280caactacaaa tactgcttag
gtttttttct aacttaattt ttaactacat catgtgaact 2340taagacattt
tcatgataaa gcattactgt agtgtcagtt ttccctcatc ctcgatcata
2400gtccttccca tgaagcaggg cccttcccct cccccccctt tgccgtttcc
ctccccacca 2460gatagtcccc tgtctgcttt aacctaccag ttagtatttt
ataaaaactg atcattggaa 2520tatttattat cagttttgtt cactgttatc
agttttgttc actaatttgt ccaataatgg 2580aattaacgtc ttctcatctg
tttgagaaag atctgaaaca aggggccatt gcaggagtac 2640atggctccag
gcttacttta tatactgcct gtatttgtgg ctttaaaaaa atgacctttg
2700ttatatgaat gctttataaa taaataatgc atgaactttt ttaaaaaaaa
aaaaaaaaaa 2760aaaaaaaaaa aa 2772866399PRTMouse 866Met Arg Ser Leu
Ser Leu Ala Trp Leu Leu Gly Gly Ile Thr Leu Leu 1 5 10 15Ala Ala
Ser Val Ser Cys Ser Arg Thr Glu Asn Leu Ala Pro Gly Arg 20 25 30Asn
Asn Ser Lys Gly Arg Ser Leu Ile Gly Arg Leu Glu Thr Gln Pro 35 40
45 Pro Ile Thr Gly Lys Gly Val Pro Val Glu Pro Gly Phe Ser Ile Asp
50 55 60Glu Phe Ser Ala Ser Ile Leu Thr Gly Lys Leu Thr Thr Val Phe
Leu65 70 75 80Pro Val Val Tyr Ile Ile Val Phe Val Ile Gly Leu Pro
Ser Asn Gly 85 90 95Met Ala Leu Trp Ile Phe Leu Phe Arg Thr Lys Lys
Lys His Pro Ala 100 105 110Val Ile Tyr Met Ala Asn Leu Ala Leu Ala
Asp Leu Leu Ser Val Ile 115 120 125Trp Phe Pro Leu Ala Ile Ala Tyr
His Leu His Gly Asn Asn Trp Val 130 135 140Tyr Gly Glu Ala Leu Cys
Lys Val Leu Ile Gly Phe Phe Tyr Gly Asn145 150 155 160Met Tyr Cys
Ser Ile Leu Phe Met Thr Cys Leu Ser Val Gln Arg Tyr 165 170 175Trp
Val Ile Val Asn Pro Met Gly His Pro Arg Lys Lys Ala Asn Ile 180 185
190Ala Val Gly Val Ser Leu Ala Ile Trp Leu Leu Ile Phe Leu Val Thr
195 200 205Ile Pro Leu Tyr Val Met Lys Gln Thr Ile Tyr Ile Pro Ala
Leu Asn 210 215 220Ile Thr Thr Cys His Asp Val Leu Pro Glu Glu Val
Leu Val Gly Asp225 230 235 240Met Phe Asn Tyr Phe Leu Ser Leu Ala
Ile Gly Val Phe Leu Phe Pro 245 250 255Ala Ile Leu Thr Ala Ser Ala
Tyr Val Leu Met Ile Lys Thr Leu Arg 260 265 270Ser Ser Ala Met Asp
Glu His Ser Glu Lys Lys Arg Gln Arg Ala Ile 275 280 285Arg Leu Ile
Ile Thr Val Leu Ala Met Tyr Phe Ile Cys Phe Ala Pro 290 295 300Ser
Asn Leu Leu Leu Val Val His Tyr Phe Leu Ile Lys Thr Gln Arg305 310
315 320Gln Ser His Val Tyr Ala Leu Tyr Leu Val Ala Leu Cys Leu Ser
Thr 325 330 335Leu Asn Ser Cys Ile Asp Pro Phe Val Tyr Tyr Phe Val
Ser Lys Asp 340 345 350Phe Arg Asp His Ala Arg Asn Ala Leu Leu Cys
Arg Ser Val Arg Thr 355 360 365Val Asn Arg Met Gln Ile Ser Leu Ser
Ser Asn Lys Phe Ser Arg Lys 370 375 380Ser Gly Ser Tyr Ser Ser Ser
Ser Thr Ser Val Lys Thr Ser Tyr385 390 3958673011DNARat
867gttaaaggaa ggggacccgg tactccgagt ggggctcgga gtttcgaacc
actggtggcg 60gattgcccgc ccgtcccacg tccggggatg cgaagtctca gcctggcgtg
gctgctggga 120ggtatcaccc ttctggcggc ctcggcctcc tgcaaccgga
ccgtgaatgc accgggaccc 180aacagtaaag ggagaagtct gattggcaga
ttggacacgc cgcctcccat cactgggaaa 240ggggctccag ttgaaccagg
cttttccgtt gatgaattct ctgcatccgt cctcaccggg 300aagctgacca
ccgtctttct cccggtcatc tacatcattg tctttgtaat tggtttgccc
360agtaatggta tggccctctg ggtcttcttc ttccgaacga agaagaagca
ccctgctgtg 420atttacatgg ccaacctggc cttggcagac ctcctctctg
tcatctggtt ccccctgaag 480atctcctacc acctccatgg caacgactgg
acctatgggg atgcgctctg caaggtgctc 540attggctttt tctacggcaa
tatgtactgc tccatccttt tcatgacctg cctcagcgtg 600cagaggtact
gggtgatcgt gaaccccatg ggacactcca ggaagagggc caacatcgct
660gttggcgtct ccctggccat ctggctcctg atttttctgg tcaccatccc
tctgtacgtc 720atgaggcaga ccatctacat tccagccttg aacatcacca
cctgtcacga cgtgctgccc 780gaggaggtcc tggtggggga catgttcagt
tacttcctct ccctggccat tggagtcttt 840ctgttcccag ccctccttac
tgcgtctgcc tacgtgctca tgatcaaaac gctccgttcc 900tccgccatgg
acgagcactc ggagaagaaa aggcggaggg ctatccgcct catcatcacg
960gtgctgtcca tgtacttcat ctgcttcgct cccagcaacg tgctgctcgt
cgtgcattat 1020ttcctcatca aaagccagag gcagagccac gtctacgccc
tctacctcgt cgccctctgc 1080ctgtccaccc tcaacagctg catagacccc
tttgtctact actttgtttc gaaagatttc 1140agggaccagg ccagaaacgc
gctcctctgc cgaagcgtcc gcaccgtgaa acgcatgcag 1200atatcgctca
cctccaacaa gttctccagg aaatccagct cttactcctc cagctcaacc
1260agtgttaaaa cctcctactg agctgggtct gaggatatgg agccagcttg
atgatgatgc 1320tggtgatgat gatgatgatg atgatggtga tgatgctgat
gatgctgatg atgctgatga 1380tgctgatgat gatgatgtat gtgtgtgcat
atgtgcgtgc atgcgtgtgt gtgtgtgtgt 1440gtgtgtgtgt gtgtgtgtgt
tagggatgca ccacaacgca cggggctgtc atttcctatc 1500caagttgcta
gtctctgtac cagtcacaag aatgatggac gtcagcgtcc gaaactgaag
1560gaaccgagag gaacatgctt tgcagaagtg aggaaggaaa ttcgttgacc
tgcagagaac 1620tacacctggc aagaaagtta agaccccccc gaaatgcttt
cttgttcatc tggagtccgt 1680catggctttg tcaggatctg agatccttgt
agagcttcag tccagctgat aatgactcta 1740tagacttgga agatgtgtct
gcgaatgagg ctcctggccg gcattccaac tggttaacac 1800tgagcttgct
ggacgacagg attcaaatgg ccacagtggt tccgttctcg catggtttca
1860tcagaactac tggggatctt gttcaatgtg caggtccctc agcctcagtg
cccagggagc 1920tcggatacga gggggccgct ctacaaactt cagtgatgtc
tgcatacaca gaaccgcaga 1980ggcgagcccc gttccgcttg ccagggcacc
gtagtgacgt tggcaaagaa aaaccaacag 2040cagtgtttga gcctcctttt
ggtcaattta tgatgaattt ccctatgggt taactgggat 2100ttctggttcc
tttattaccc ctttgtagtt ttatatgtct gtaagtcaac aaaatgaggc
2160tcctaaacat gtaaataaaa attttgttta ttttttttaa ttttacataa
gtcagtgtgg 2220gtaatagagt attaggccga ctgcaaatac tgcttagttt
ttttctaagt taatttttaa 2280atacatcatg caaacttaag acattttcat
gataaagcac tattacagtg tcagttccct 2340tctccctcag tcatatgcct
tcccgggatg ctggcccttc ccctcctctc cttcccccct 2400tgccttcccc
ctccccccag atagccagtg tgccttcatg taccatttag tattttataa
2460aaaccgtcgt tgaaatattt attatcagtt ttgttcacct tttaccgtcc
attgaatgaa 2520cgtcttctcg tctgtttggg caagagcagg aacaagaggc
tacggccatt gcaggggtac 2580gtggttccag acttacttta tataccgcct
ggatctgcgg cttgagaaat taccttgtac 2640gaaggctttc taaataatgt
ataacccttg accttttttt ttttaaacaa cttctttcca 2700gctgtgtgtt
cttttgtaga aggaggagga gaagggaatc cccctgttgt agatacagtg
2760atctgatcac cctatcctgt tctgttcttt cttcctttct tctttaacac
agtgcgatgc 2820ccaccccacc actttccagt ccttccttct tccttctttc
cttcctttct tctctttcca 2880caacactagg gatctaaacc tagccttgtg
aatttacact ttttccccca cactagtttt 2940tctaataaac aaaatgtagt
tcacgttgct ccacaaaaaa aaaaaaaaaa aaaaaaaaaa 3000aaaaaaaaaa a
3011868397PRTRat 868Met Arg Ser Leu Ser Leu Ala Trp Leu Leu Gly Gly
Ile Thr Leu Leu 1 5 10 15Ala Ala Ser Ala Ser Cys Asn Arg Thr Val
Asn Ala Pro Gly Pro Asn 20 25 30Ser Lys Gly Arg Ser Leu Ile Gly Arg
Leu Asp Thr Pro Pro Pro Ile 35 40 45 Thr Gly Lys Gly Ala Pro Val
Glu Pro Gly Phe Ser Val Asp Glu Phe 50 55 60Ser Ala Ser Val Leu Thr
Gly Lys Leu Thr Thr Val Phe Leu Pro Val65 70 75 80Ile Tyr Ile Ile
Val Phe Val Ile Gly Leu Pro Ser Asn Gly Met Ala 85 90 95Leu Trp Val
Phe Phe Phe Arg Thr Lys Lys Lys His Pro Ala Val Ile 100 105 110Tyr
Met Ala Asn Leu Ala Leu Ala Asp Leu Leu Ser Val Ile Trp Phe 115 120
125Pro Leu Lys Ile Ser Tyr His Leu His Gly Asn Asp Trp Thr Tyr Gly
130 135 140Asp Ala Leu Cys Lys Val Leu Ile Gly Phe Phe Tyr Gly Asn
Met Tyr145 150 155 160Cys Ser Ile Leu Phe Met Thr Cys Leu Ser Val
Gln Arg Tyr Trp Val 165 170 175Ile Val Asn Pro Met Gly His Ser Arg
Lys Arg Ala Asn Ile Ala Val 180 185 190Gly Val Ser Leu Ala Ile Trp
Leu Leu Ile Phe Leu Val Thr Ile Pro 195 200 205Leu Tyr Val Met Arg
Gln Thr Ile Tyr Ile Pro Ala Leu Asn Ile Thr 210 215 220Thr Cys His
Asp Val Leu Pro Glu Glu Val Leu Val Gly Asp Met Phe225 230 235
240Ser Tyr Phe Leu Ser Leu Ala Ile Gly Val Phe Leu Phe Pro Ala Leu
245 250 255Leu Thr Ala Ser Ala Tyr Val Leu Met Ile Lys Thr Leu Arg
Ser Ser 260 265 270Ala Met Asp Glu His Ser Glu Lys Lys Arg Arg Arg
Ala Ile Arg Leu 275 280 285Ile Ile Thr Val Leu Ser Met Tyr Phe Ile
Cys Phe Ala Pro Ser Asn 290 295 300Val Leu Leu Val Val His Tyr Phe
Leu Ile Lys Ser Gln Arg Gln Ser305 310 315 320His Val Tyr Ala Leu
Tyr Leu Val Ala Leu Cys Leu Ser Thr Leu Asn 325 330 335Ser Cys Ile
Asp Pro Phe Val Tyr Tyr Phe Val Ser Lys Asp Phe Arg 340 345 350Asp
Gln Ala Arg Asn Ala Leu Leu Cys Arg Ser Val Arg Thr Val Lys 355 360
365Arg Met Gln Ile Ser Leu Thr Ser Asn Lys Phe Ser Arg Lys Ser Ser
370 375 380Ser Tyr Ser Ser Ser Ser Thr Ser Val Lys Thr Ser Tyr385
390 39586922PRTArtificial SequenceSynthetic 869Gly Pro Asn Ser Lys
Gly Arg Ser Leu Ile Gly Arg Leu Asp Thr Pro 1 5 10 15Gly Gly Gly
Gly Ser Lys 2087023PRTArtificial SequenceSynthetic 870Gly Arg Asn
Asn Ser Lys Gly Arg Ser Leu Ile Gly Arg Leu Glu Thr 1 5 10 15Gln
Gly Gly Gly Gly Ser Lys 2087124PRTArtificial SequenceSynthetic
871Gly Thr Asn Arg Ser Ser Lys Gly Arg Ser Leu Ile Gly Lys Val Asp
1 5 10 15Gly Thr Gly Gly Gly Gly Ser Lys 2087224PRTArtificial
SequenceSynthetic 872Gly Thr Asn Arg Ser Ser Lys Ala Arg Ser Leu
Ile Gly Lys Val Asp 1 5 10 15Gly Thr Gly Gly Gly Gly Ser Lys
2087324PRTArtificial SequenceSynthetic 873Gly Thr Asn Arg Ser Ser
Lys Gly Ala Ser Leu Ile Gly Lys Val Asp 1 5 10 15Gly Thr Gly Gly
Gly Gly Ser Lys 2087424PRTArtificial SequenceSynthetic 874Gly Thr
Asn Arg Ser Ser Lys Gly Arg Ala Leu Ile Gly Lys Val Asp 1 5 10
15Gly Thr Gly Gly Gly Gly Ser Lys 2087524PRTArtificial
SequenceSynthetic 875Gly Thr Asn Arg Ser Ser Lys Gly Arg Ser Ala
Ile Gly Lys Val Asp 1 5 10 15Gly Thr Gly Gly Gly Gly Ser Lys
2087624PRTArtificial SequenceSynthetic 876Gly Thr Asn Arg Ser Ser
Lys Gly Arg Ser Leu Ala Gly Lys Val Asp 1 5 10 15Gly Thr Gly Gly
Gly Gly Ser Lys 2087724PRTArtificial SequenceSynthetic 877Gly Thr
Asn Arg Ser Ser Lys Gly Arg Ser Leu Ile Ala Lys Val Asp 1 5 10
15Gly Thr Gly Gly Gly Gly Ser Lys 2087824PRTArtificial
SequenceSynthetic 878Gly Thr Asn Arg Ser Ser Lys Gly Arg Ser Leu
Ile Gly Ala Val Asp 1 5 10 15Gly Thr Gly Gly Gly Gly Ser Lys
2087924PRTArtificial SequenceSynthetic 879Gly Thr Asn Arg Ser Ser
Lys Gly Arg Ser Leu Ile Gly Lys Ala Asp 1 5 10 15Gly Thr Gly Gly
Gly Gly Ser Lys 2088024PRTArtificial SequenceSynthetic 880Gly Thr
Asn Arg Ser Ser Lys Gly Arg Ser Leu Ile Gly Lys Val Ala 1 5 10
15Gly Thr Gly Gly Gly Gly Ser Lys 2088124PRTArtificial
SequenceSynthetic 881Gly Thr Asn Arg Ser Ser Lys Gly Arg Ser Leu
Ile Gly Lys Val Asp 1 5 10 15Ala Thr Gly Gly Gly Gly Ser Lys
2088224PRTArtificial SequenceSynthetic 882Gly Thr Asn Arg Ser Ser
Lys Gly Arg Ser Leu Ile Gly Lys Val Asp 1 5 10 15Gly Ala Gly Gly
Gly Gly Ser Lys 2088320PRTArtificial SequenceSynthetic 883Gly Arg
Asn Asn Ser Lys Gly Arg Ser Leu Ile Gly Arg Leu Glu Thr 1 5 10
15Gln Pro Pro Ile 2088420PRTArtificial SequenceSynthetic 884Ser Leu
Ile Gly Lys Val Asp Gly Thr Ser His Val Thr Gly Gly Gly 1 5 10
15Gly Gly Ser Lys 2088520PRTArtificial SequenceSynthetic 885Ser Leu
Ile Gly Lys Ala Asp Gly Thr Ser His Val Thr Gly Gly Gly 1 5 10
15Gly Gly Ser Lys
2088620PRTArtificial SequenceSynthetic 886Ser Leu Ile Gly Lys Val
Ala Gly Thr Ser His Val Thr Gly Gly Gly 1 5 10 15Gly Gly Ser Lys
2088720PRTArtificial SequenceSynthetic 887Ser Leu Ile Gly Lys Ala
Ala Gly Thr Ser His Val Thr Gly Gly Gly 1 5 10 15Gly Gly Ser Lys
20
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